CA2075639A1 - Triazole angiotensin ii antagonists incorporating a substituted benzyl element - Google Patents

Triazole angiotensin ii antagonists incorporating a substituted benzyl element

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Publication number
CA2075639A1
CA2075639A1 CA002075639A CA2075639A CA2075639A1 CA 2075639 A1 CA2075639 A1 CA 2075639A1 CA 002075639 A CA002075639 A CA 002075639A CA 2075639 A CA2075639 A CA 2075639A CA 2075639 A1 CA2075639 A1 CA 2075639A1
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alkyl
phenyl
aryl
substituted
methyl
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CA002075639A
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French (fr)
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William J. Greenlee
Arthur A. Patchett
David Hangauer
Wallace Ashton
Kenneth J. Fitch
Thomas Walsh
Ralph A. Rivero
Daljit S. Dhanoa
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Merck and Co Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D249/12—Oxygen or sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Substituted triazoles attached through a methylene bridge to novel substituted phenyl derivatives of formula (I) are useful as angiotensin II antagonists.

Description

2 0~7 ~ ~ 3 9 PCr/lJS91/00963 ,, , "~.

TITLE OF T~E lNVENTIO~

TRIAZOLE ANGIOTENSIN II ANTAGONISTS INCORPORATING A

SUBSTITUTED ~ENZYL ELEMENT

~ACKGROUND OF T~E INVENTION
The present application is a continuation in part of Serial No 479,779 filet on Febuary 13, 1990.

The Renin-angiotensin system ~RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension dcvelopment and maintenance as well as congestive heart ~ailure. Angiotensin II (A II), is a~ octapcptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood ve66els of lun~, ~idney, and many other organs. It i 8 the end product of the renin-angiotensin system (RAS) and is a powerful arterial vasoconstrictor that eserts it6 action by interacting with specific receptors pre8ent on cell membranes.
.

~ , : - . , ' :.

':

wos~/llsl~s 2 0:7 ~ & 3 ~ PCT/US91/0096~ ~

One of the pos6ible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analog6 of A II are known to inhibit the effect of this hormone by competitively bloc~ing the receptors, but their e~perimental and clinical applications have been limited by partial agonist activity and la.c~ of oral absorption ~M. Antonaccio. Clin. Ex~.
~y~erten~. A4, 27-46 (1982); D. ~. P. Streeten and G. ~. Anderson, Jr. - ~n~ook of ~y~eL~nEion, C~inical ~harma~olo~y of Antihy~ ensive D~e~, ed.
A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].
Recently, several 6ubstituted imidazoles have been described as A II antagoni6ts.
Illustrative of such compounds are those disclosed in U.S. Patents 4,207,324; 4,340,598; 4,576,958; and 4,582,847; and 4,B80,~04 in European Patent Applications 028,834; 245,637; 253,310; 291,969; and 324,377 and in articles by A.T. Chiu, ~ 1. tEur. J
~h~mh E~. The~2~ 7, 13-21 (1988)] and by P.C.
Wong, ~ ~1- tJ Pha~ml E~_ The~a~, 2~1.
1-~(1988)]. All of the ~.S. Patents, European Patent Applications 028,834 and 253,310 and the two articles disclose substituted imidazole compounts which are generally bonded through a lower alkyl bridge to a substituted phenyl. European Patent Application 245,637 discloseR derivatives of 4,5,6,7-tetrahydro-2~-imidazo~4,5-~]-pyridine-6-carbo~ylic acid and analo~s thereof as antihypertensive agents.
The compounds disclosed within this application have not been identified in any US
Patents, European Applications or articles. The compounds of the present invention are substituted , WO 91/1 1909 2 0.7 5 ~ ~ 9 - p~/US91/00963 triazoles which are bonded through a methylene bridge to a novel substituted phenyl element. DuPont also has filed a European Application (EP0 0,323,841) covering substituted pyrroles, pyrazoles and triazoles. The present invention covers novel antagonists which incorporate a novel substituted benzyl element linked to the triazole moiety. The above cited applications are hereby incorporated by reference, serving as an information source as to the preparation of 6ubstituted triazoles. A pending Merck application, Serial No. 382,138, discloses other novel triazoles and the 6ynthetic routes to these triazoles are described in the Schemes I-l through I-14 and the incorporation of the 6ustituted benzyl element is de6cribed in Schemes I-15 through I-30.
The compounds of this invention have central nervous ~ystem (CNS) activity. They are useful in the treatment of cognitive dy6functions including Alzheimer~ E disea6e, amne6ia and senile dementia.
These compounds al60 have an~iolytic and antidepressant propertie6 and are therefore, useful in the relief of 6ymptoms of anxiety and tension and in the treatment of patients with depressed or dysphoric mental 6tate6.
In addition, these compounds e~hibit antidopaminergic properties and are thus u6eful to treat disorder6 that involve dopamine dysfunction such as 6chizophrenia. The compounds of this invention are especially u8eful in the treatment of these conditions in patients who are al60 hypertensive or have a congestive heart failure condition.

.....

wos~ gog 2 0 7 ~ ~`3 ~ PCT/US91~00963 ~

DET~ILE~ DE~~I~TION OF TH~ I~VENTIQ~
This invention relate6 to compounds of Formula I:

N, ~ ~ T)b-R
R'-~ ~

R9 ~ Rl X~z Rll y--R12 FORMULA I
Wherein Rl is:
~a) (Cl-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which i6 unsubstituted or substituted with one or more 6ub6tituent~ selected from the group consi6ting of:
i) ~ryl, wherein aryl i6 defined as phenyl os naphthyl, un6ub6tituted or 6ubstituted with l or 2 6ub6tituents selected from the group con~isting of:
l) Cl, Br, I, F, 2) (Cl-C4)-alkyl, 3) (Cl-C4)-alko~y, 4) N02 5) CF3 6) S02NR2aR2a, 7) (Cl-C4)-alkylthio, , wo9l/1]909 ~7~`3~
8) hydro~y, 9) amino, 10) (C3-C7~-cycloalkyl, ll) (C3-ClO)-alkenyl; and S ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, or i v ) COOR2, v) -CF2CF3. or vi) -C~2CF3; and (b) perfluoro-(Cl-C4)-alkyl, or (c) (C3-C6)-cycloalkyl, unsubstituted or substituted with one or more substituents from the group consi6ting of:
(Cl-C4)-alkoxy, (Cl-C4)-alkyl- thio, perfluoro-(Cl-C4)-alkyl, hydroxy, or F, Cl, ~r, I: and B ~s:
(a) a single bond, (b) -S(O)n(C~2)~-, or (c) -0-;and n i6 0 to 2; and 6 i6 0 to 5; and R2 is:
(a) ~, or (b) (Cl-C6)-alkyl; and ~ ' .
- : .

wo 9""gog 2 0 7 ~ 6 3 9 PCT/US91/00963 ~

R2a i 6 (a) R2, (b) C82-aryl, or (c) aryl; and (d) when R2 and R2a are alkyl ~ubstituent~ on the same nitrogen they can be joined to form a ring; and wherein there is more than one R2a group in the definition of a structure of Formula I they may be the same or different; and R9 and R10 are independently:
(a) 8, (b) (Cl-C6)-alkyl, unsubstituted or substituted with (C3-C7)-cycloalkyl, ( c ) ( C2-C6 ) -alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, I, (f) (Cl-C6)-alko~yl, (g) when R9 and R10 are on adjacent carbons, they can be joined to form an phenyl ring, (h) perfluoro-(Cl-C6)-alkyl, (i) (C3-C7)-cycloalkyl, unsubstituted or substituted with (Cl-C6)-alkyl, (;) aryl; and X is:
(a) _o_, (b) ~5(0)n~~
(c ) -nRl3_ (d) -C820-, .

:

~-.WO~1/11909 ~ Q ~
G~ Pcr/US9l/00963 , ~

(e) -C~2S(O)n~, (f) -C~2NR13-, (g) -OC~2-.
(h) -NR13C~2-.
(i) -s(o) ( j ) -C~l2- , (k) -(C~2)2-' (1) single bond, or (m) -C~=, wherein Y and R12 are absent forming a lo -C=C bridge to the carbon bearing Z and Rll; and Y is:
(a) single bond, (b) _o_, (C) ~S(O)n~, (d) _NR13_ or (e) -C~2-; and Except that X and Y are not defined in such a way that the carbon atom to which Z is attached also 6imultaneously i8 bonded to two heteroatoms (0, N, S, SO . SO2 ) .

Rll and R12 are independently:
(a) E.
(b~ ~Cl-C6)-alkyl unsub6tituted or 6ubstituted with:
(i) aryl, or (ii) (C3-C7)-cycloal~yl, (c) aryl, unsubstituted or substituted with 1 to 5 substitute~ts selected from the group consisting of:

' , ' ., WO91/11909 ~2 ~ 7 ~
~ ~ ~ J PCT/US91/00963 i) Cl, Br, I, F, ii) (Cl-C4)-alkyl, iii) t(cl-cs)-alkenyl]c~2 iv) [ (Cl-C5 )-alkYnYl~C~2- .
v) (Cl-C4)-alko~y, or vi) (Cl-C4)-al~ylthio, and (d) aryl-(Cl-C2)-alkyl, wherein the aryl group i~ unsub6tituted or ~ubstituted with l to 5 6ubstitutents selected from the group consisting of:
i) Cl, Br, I, F, i i ) ( Cl-C4 )-al~yl .
iii) [(Cl-C5)-alkenyl]C~2-, iv) [ (Cl-C5 )-alkYnYl~C~2- .
v) (Cl-C4)-alko~y, or vi) (Cl-C4)-al~ylthio. and (e) (C3-C7)-cycloal~yl; and Rl3 is:
(a) ~, (b) (Cl-C6)-al~yl, (c) aryl, (d) aryl-(Cl-C6)-alkyl-(C=0)-, (e) (Cl-C6)-alkyl-(CeO)-, (f) t(C2-Cs)-alkenyl~C~2-, ( g ) r (C2-Cs)-alkynyl]C~2-, or (h) aryl-C~2-, and Z is:
(a) -C02~, (b) -C02-(Cl-C6)-alkyl, - (c) -tetrazol-5-yl, (d) -C0-NB(tetrazol-5-yl) ,., - ~ , : -,. :. , . ... . ,~.

. wos1~]1sos 207 639 ~ PCT/VS91/00963 ~ .~

(e) -CON~-S02-aryl, (f) -CON~-S02-(Cl-CB)-alkyl, wherein the alkyl group is unsub6tituted or substituted with a substituent chosen from the group consi~ting of: -0~, -SH, -O(Cl-C4)-alkyl, - -S (Cl-C4)-al~Yl~ -CF3, Cl, Br, F, I, -N02, -C02H~ -co2-(cl-c4)-alkyl~ -N~2, -N~t(Cl-C4)-alkyl], -N[(Cl-C4)-alkyl]2; and (g) -COM~-S02-perfluoro-(Cl-C4)-alkyl, (h) -CONH-S02-heteroaryl, or (i) -CON~S02NR2aR2a; and ( j ) -S02NHCO-aryl, (k) -S02MCC0-(Cl-C8)-alkyl. wherein the alkyl group is unsubstituted or ~ubstituted with a lS sub6tituent chosen from the group consisting of: -OH, -S~, -O(Cl-C4)-alkyl, -S-(Cl-C4)-alkyl, -CF3, Cl, Br, F, I, -N02, -CO2~, -co2-(cl-c4)-alkyl, -N~2, -N~t(Cl-c4)-alkyl]~ -N~(Cl-C4)-alkyl]2; and (l) -S02N~CO-(Cl-C4)-perfluoroalkyl, (m) -S02N~CO-heteroaryl. or (n) -S02N~CONR2aR2a; and T is ~S(O)n~~ --. -N~CH2-, -N~C(=0) , -C(.O)N(R20)-~ or -N(R20)-; and b is 0 or l; and R15 i S
(a) ~, (b) (Cl-C6)-alkyl, (c) phenyl, or (d) benzyl; and wo 9~ gog 2iO`7 ~ 3 ~
. PCT/US91/00963 ~

R16 i6 (a) (Cl-ClO)-alkyl;
(b) substituted (Cl-C10)-alkyl in which one or more substituent(s) is selected from (1) ~, Br, Cl, F, (2) hydro~y, (3) (Cl-ClO)-alkoxy, (4) (Cl-C5)-alko~ycarbonyl, (5) (Cl-C5)-acyloxy, (6) (C3-C8)-cycloalkyl, (7) aryl, (8) substituted aryl in which the substituents are V and W, (9) (cl-clo)-alkyl-s(o)n lS (lO) (C3-Cg)-cycloal~yl-s(o) (11) phenyl-S(O)n~
(12) substituted phenyl-S(O)n in which the substituents are V and W, (13) oxo, (14) carboxy, (15) NR2R2a, (16) (Cl-C5)-alkylaminocarbonyl, (17) di(Cl-C5)-alkylaminocarbonyl, or (18) cyano, (c) perfluoro-(Cl-C4)-alkyl, (d) (C2-C10)-alkenyl, (e) (C2-ClO)-alkynyl, (f) (C3-Cg)-cycloalkyl, (g) sub~tituted (C3-C8)-cycloalkyl in which the ~ubstituent i~ selected from:
(l) (Cl-C5)-alkyl, or (2) (Cl-C5)-alkoxy, .
.
. ~ .

, . WO 91/11909 ~ U,7,~
, PCI`/US91/00963 (3) (Cl-C5)-alko~ycarbonyl, (4) (Cl-C5)-acyloxy, t5) (Cl-Cs)-acyl, (6) hydro~y, (7) Br, Cl, F, I, (8) (C3-C8)-cycloalkyl, (9) aryl, (10) substituted aryl in which the ~ubstituents are V and W, (11) (Cl-Clo)-alkYl~S(O)n~
(12) (C3-C8)-cycloalkyl-S(O)n.
(13) phenyl-S(O)n, (14) substituted phenyl-S(O)n in which the substituents are V and W, (15) oxo, (16) carboxy, (17) NR2R2a (18) (Cl-C5)-alkylaminocarbonyl, (19) di(Cl-Cs)-alkylaminocarbonyl, or (20) cyano, (h) C02R2a, (i) aryl, (j) substituted aryl in which the substituents are V and W, (k) aryl-(C~2)r-~Ml)z~(C~2)t-(1) substituted aryl-(CB2)r-(Ml)z-(CB2)t- in which the aryl group is substituted with V
and W, WOg~ 9O9 207~39 Pcr/US9 1 /00963 ~
W

(~ V~(CHz)r--(~)z--(CH2)t--~

(n) ~CH2)~)s--(CH~)t--, V ~,,W
( ) ~4 CH2) r ~ ( CH2) t--, (P) W~CH2)r ~M~)z~CH2)t--, or (q) w~N
5 ~ (CH2)r--~(CH2)t ~ ~nd Ml is ' S, -~R15)-, or -C(0)-; and z i s 0 or 1; and 2S r and t are 0 to 2; and V and W are each independently selected from:
(a) ~, ' (b) (Cl-C5)-al~oxy, (c) (C1-Cs)-alkyl, (d ) hydroxy, (e) ((Cl-Cs)-alkYl)S(O)n~

- - , .
, . ~

- ; . -. ~ . :
.. ,, - ' . : : -f WO 91/11909 2 ~-7 S ~ 3 ~ pCTJUS91~00963 (f) -CN, (g) -N02 ~
(h) -NR2R2-a, (i) [(Cl-C5)-alkyl)~C0-NR2R2a, (j) -C02R2a, (k) t(Cl-Cs)-al~yl)]Co-, (l) CF3, (m) I, Br, Cl, F, (n) hydroxy-(Cl-C4)-alkyl-, (O) carbo~cy-(Cl-C4)-alkyl-, (p) -tetrazol-5-yl, (q ) -NEI-S02CF3, (r) aryl, ( S ) -O-CONR2R2a lS (t) NR2a_c02R2a (u ) -NR2a-coNR2aR2a (~) _NR2a-CON(C~2C~2)2Ql~
(w) -0CON(C~2C~2)2Ql~ or (x) -CONR2R2a; and Ql is:
0, S(O)n, or NR2a; and Rl8 i6 (a) phenyl, unsub6tituted or sub6tituted with:
V and W, (b) . (Cl-C4)-al~yl, or (c) perfluoro-(Cl-C4)-alkyl; and R20 is (a) ~, (b) (Cl-C6)-alkyl, ..

WO91~]1909 2 0 7 5 ~ ~ ~ PCT/US91/OOg63~

(c) allyl, (d) (C3-C6>-cycloalkyl, (e) (Cl-C4)-acyl, (f) benzyl, or (g) phenyl; and R24 groups are independently:
(a) ~, (b) (Cl-C6)-al~Yl. (C2-C6)-alkenyl or lo (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of: (C3-C7)-cycloalkyl, Cl, Br, , ~, 0~, -NR2, -M~[(Cl-C4)-alkyl].
-N[(Cl-C4)-alkyl]2, -N~So2R25, -Co2R25, (Cl-C4)-alkosyl, (Cl-C4)-alkylthio, (Cl-C4)-acyl~ or C(=O)N~2, (c) aryl, unsubstituted or substituted with V or W, (d) aryl-(Cl-C4)-alkyl, unsubstituted or 6ub~tituted with V or W, R25 is:
(a) ~.
(b) (Cl-C6)-alkyl, (c) aryl, or (d) aryl-(Cl-Cs)-alkyl; and the pharmaceutically acceptable salts thereof.

, - ' ~.

, wos~ sog 2 0 7 ~ ~ 3 ~ ` PCT/US91/00963 ,~, The al~yl substituten~6 recited above denote straight and branched chain hydrocarbons of the length specified 6uch as methyl, ethyl, isopropyl, isobutyl, neopentyl, isopentyl, etc.
The alkenyl and alkynyl substituents denote alkyl groups as describet above which are modified BO that each contains a carbon to carbon double bond or triple bond, respectively, such as vinyl, allyl and 2-butenyl.
Cycloalkyl denotes rings compo6ed of 3 to 8 methlene groups, each which may be substituted or unsubstitued with other hydrocarbon 6ubstituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
The alkoxy 6ubstituent repre6ents an alkyl group as described above attached through an oxygen bridge.
The aryl 6ubstituent recited above represents phenyl or naphthyl.
The heteroaryl substituent recited above represent6 any 5- or 6-membered aromatic ring containing from one to three heteroatoms selected from the group con6isting of nitrogen, oxygen, and sulfur, for example, pyridyl, thienyl, furyl, imidazolyl, and thiazolyl.
~S

wo9l~llso9 2 0 7 ~ ~ 3 9 PCT/US91/00963 ~,;

The preferred compounds of this invention are:

3-Butyl-4-[[4~ carboxy-1-phenylmethoxy)phenyl]-methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-triazole.

3-Butyl-4-r[4-(1-carboxy-1-phenylmethoxy)phenyl]
methyl]-5-(4-nitrobenzylsulfinyl)-4~-1,2,4-triazole.

3-Butyl-4-[t4-[l-carbo~y-1-(2-chlorophenyl)methoxy]-lo phenyl~methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-triazole 3-Butyl-4-[[4-[1-carboxy-1-(2-methylphenyl)methoxy]-phenyl]methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-triazole~
3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)phenyl]-methyl]-5-(4-methoxybenzylthio)-4~-1,2~4-triazole.

3-Butyl-4-r[4-(1-carboxy-1-phenylmethoxy)phenyl]-methyl]-5-(4-methoxybenzylsulfinyl)-4~-1,2,4-triazole.

3-Butyl-4-[[4-[l-carboxy-1-(2-chlorophenyl)methoxy]-phenyl]methyl]-5-(4-methoxybenzylthio)-4~-1,2,4-triazole.
3-Butyl-4-[[4-[1-carboxy-1-(2-methylphenyl)methoxy]-phenyl]methyl]-5-(4-methoxybenzylthio)-4~-1,2,4-triazole.

3-Butyl-5-(2-carbo~ybenzylthio)-4-[[4-(1-carboxy-1-phenylmethoxy)phenyl~methyl-4~-1,2,4-triazole.

. - . ~ . . .

~ w091/1l~09 2 0 7 ~ & 3 9 PCT/~S9"00963 3-Butyl-5-(2-carboxybenzylthio)-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy3phenyl~methyl]-4~-1,2,4-triazole.

3-Butyl-5-(2-carboxybenzylthio)-4-[[4-[l-carbosy-1-(2-methylphenyl)methosy~phenyl]methyl]-4~-1,2,4-triazole.

3-Butyl-4-[t4-[1-carboxy-1-phenylmethoxy]phenyl~-methyl~-5-(4-chlorobenzylthio)-4~-1,2,4-triazole.

10 3-Buty'-4-t[4-[1-carboxy-1-(2-methylphenyl)methoxy~-phenyl]methyl~-5-(4-chlorobenzylthio)-4~-1,2,4-triazole.

3-Butyl-4-[[4-[1-carbosy-1-phenylmethoxy]phenyl]-15 methyl~-5-(4-methylbenzylthio)-4~-1,2,4-triazole.

3-9utyl-4-[[4-[l-carboxy-1-(2-chlorophenyl)methoxy]-phenyl~methyl~-5-(4-methylbenzylthio)-4~-1,2,4-triazole.

3-Butyl-5-(4-nitrobenzylthio)-4-[[4-[1-phenyl-1-(5-tetrazolyl)methoxy~phenyl~methyl~-4~-1,2,4-triazole.

25 3-Butyl-4-t[4-tl-phenyl-1-(5-tetrazolyl)methoxy~-phenyl]methyl]-5-(4-nitrobenzylsulfinyl)-4~-1,2,4-triazole.

3-Butyl-4-[[4-[1-(2-chlorophenyl)-1-(5-tetrazolyl)-methoxy]phenyl~methyl]-5-(4-nitrobenzylthio)-4E-1,2,4-triazole.

~ .: .

WO91/11909 2 0 7 5 ~ j.3 ~ -` P~T/US91/00963 ~

3-Butyl-5-(4-methoxybenzylthio)-4-[[4-[1-phenyl-1-(5-tetrazolyl)methoxy]phenyl]methyl3-4~-1,2,4-triazole.

3-Butyl-5-(4-metho~ybenzylthio)-4-[t4-rl-(2-chloro-phenyl)-1-(5-tetrazolyl)methoxy]phenyl]methyl]-4~-1,2,4-triazole;

3-Butyl-5-(4-methoxybenzylthio)-4-t[4-[1-(2-methyl-phenyl)-1-(5-tetrazolyl)methoxy]phenyl~methyl]-4~-1.2,4-triazole 3-Butyl-5-(2-carbo~ybenzylthio)-4-[[4-[1-phenyl-1-(5-tetrazolyl)methoxy]phenyl]methyl]-4~-1,2,4-triazole.

3-Butyl-5-(2-carboxybenzylthio)-4-r[4-rl-(2-chloro-phenyl)-l-(5-tetrazolyl)methoxy]phenyl]methyl-4~-1,2,4-triazole.

3-Butyl-5-(4-chlorobenzylthio)-4-[[4-[1-phenyl-1-(5-tetrazolyl)methoxy]phenyl~methyl]-4 -1,2,4-triazole.

3-~utyl-5-(4-chlorobenzylthio)-4-t~4-~1-(2-chloro-phenyl)-1-(5-tetrazolyl)methoxy]phenyl]methyl]-4~-1,2,4-triazole.
3-Butyl-4-[[4-~1 carboxy-1-(2,6-dichlorophenyl)-metho~y~phenyl~methyl]-5-(4-methoxybenzylthio)-4~-1,2 4-triazole.

3-Butyl-4-tt4-rl-carboxy-1-(2-methoxyphenyl)methoxy~-phenyl~methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-triazole.

.
:. , - ~ . . . -- - -.
.
:
, ' ': ` -`. ~ : ' , . wo g~ go9 2 ~7~ ~ 3 ~ P~/Ussl/oo963 3-Butyl-4-tt4-t(l-carboxy-1-phenylmethyl)amino]-phenyl~methyl]-5-(4-methosybenzylthio)-4a-1,2,4-triazole.

3-Butyl-4-tt4-ttl-carboxy-1-(2-chlorophenyl)methyl]-amino]phenyl]methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-triazole.

3-Butyl-4-tt4-(1-carboxy-1-phenylmethoxy)phenyl]-methyl]-5-(4-chlorobenzylsulf iDyl )-4~-1,2,4-triazole.

3-Butyl-4-tt4-tl-carboxy-1-(2-chlorophenyl)methosy]-phenyl]methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-triazole.

3-Butyl-4-tt4-tl-carbo~y-1-(2-chlorophenyl)methoxy~-phenyl]methyl]-5-(4-chlorobenzylsulfinyl)-4~-1,2,4-triazole.

3-Butyl-4-tt4-(1-carbo~y-1-phenylmethosy)-3-propylphenyl]methyl]-5-phenyl-4~-1,2,4-triazole.

3-Butyl-4-t[4-(1-carbo~y-1-phenylmetho~y)-3-propylphenyl]methyl]-5-(4-chlorobenzylthio)-4~-1.2.4-triazole, 3-~utyl-4-t[4-(1-carbosy-1-phenylmethosy)_3_ propylphenyl]metbyl]-5-(4-metho2ybenzylthio)-4~-1,2,4-triazole.

3-Butyl-4-tt4-tl-carbosy-1-(2-chlorophenyl)metho2y]-3-propylphenyl]methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-triazole.

-, ., Wo9]/11909 2 ~7 S 6 3 ~ PCT/US91~00963 ~

3-Butyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]-3-propylphenyl~methyl]-5-(4-methoxybenzylthio)-4~-1,2,4-triazole.

3-Butyl-4-tt4-tl-carboxy-1-~2-methylphenyl)methoxy~-3-chlorophenyl]methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-triazole.

3-Butyl-4-tt4-(1-carboxy-1-phenylmethoxy)-3,5-~o dipropylphenyl]methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-triazole.

3-Butyl-4-t[4-(1-carboxy-1-phenylmethoxy)-3,5-dipropylphenyl]methyl]-5-(4-methoxybenzylthio)-4~-1.2,4-triazole.
3-Butyl-4-[[4-tl-carboxy-1-(2,5-dibromo-3,4-dimethoxyphenyl)methoxy~phenyl]methyl]-5-(4-chloro-benzylthio)-4~-1,2,4-triazole.

3-Butyl-4-t~4-~1-carbo~y-1-(2.5-dibromo-3,4-dimethoxyphenyl)methoxy]phenyl]methyl]-5-(4-metho~y-benzylthio)-4~-1,2,4-triazole.

3-Butyl-5-(2-carboxybenzylthio)-4-tt4-(1-carboxy-1-phenylmetho~y)-3-propylphenyl]methyl]-4~-1,2,4-triazole.

3-Butyl-5-(2-carboxybenzylthio)-4-[[4-(1-carbo~y-1-(2-chlorophenyl)methoxy]-3-propylphenyl]methyl]-4~-1,2,4-triazole.

-; ' .................... . :
. . . .
': . .................... . , ' :
.

WO91/11909 2 ~ 7,3 5 3;9 `: P~T/US91/00963 3-Butyl-5-(2-carboxybenzylthio)-4-~t4-(1-carboxy-1-(2-methylphenyl)methoxy]-3-chlorophenyl]methyl]-4~-1,2,4-triazole.

3-Butyl-5-(2-carbosybenzylthio)-4-[[4-(1-carboxy-1-phenylmethoxy)-3,5-dipropylphenyl]methyl]-4~-1,2,4-triazole.

3-Butyl-5-(2-carboxybenzylthio)-4-[[4-tl-carboxy-1-(2,5-dibromo-3,4-dimethoxyphenyl)methoxy]phenyl]-methyl]-4~-1,2,4-triazole.

4-[~N-Allyl-N-[(l-carboxy-l-phenyl)methyl]amino]-phenyl]methyl]-3-butyl-5-(4-chlorobenzylthio)-4~-1.2.4-triazole 4-[ r tN-Allyl-N-[(l-carboxy-l-phenyl)methyl]amino]-phenyl]methyl]-3-butyl-5-(4-methoxybenzylthio)-4~-1,2,4-triazole 4-t~tN-Allyl-N-[(l-carboxy-l-phenyl)methyl]amino]-phenyl]methyl~-3-butyl-5-(2-carboxybenzylthio)-4~-1,2,4-triazole 2-~utyl-4-~t[N-t(l-carboxy-l-phenyl)methyl]-N-ethylamino~phenyl]methyl]-5-(4-chlorobcnzylthio)-4~-1,2,4-triazole W091/11909 2 Q 7 ~ 6 3 9 PCT/US9l/00963 ~

Preparation of 3,4,5-trisubstituted-1,2,4-triazole~ (Formula I) The compound~ of Formula I can be prepared by a variety of methods typified by those described below. General synthetic method~ for 3,4,5-tri6ub-6tituted 1,2,4-triazoles are discussed in book~ or review articles ~uch as:
lo (1) C. Temple and J.A. Montgomery, ~'Triazole~:
1,2,4" (Vol. 37 of "The Chemistry of ~eterocyclic Compounds", A. Weis6berger and E.C. Taylor, eds.), Wiley-Interscience, New Yor~, 1981.
lS (2) J.B. Polya, in "Comprehensive ~eterocyclic Chemistry. The Structure, Reactions, Synthe~is and Uses of ~eterocyclic Compound 8", A.R. Katritz~y and C.W. Rees, ed~., Vol. 5, Pergamon Press, Oxford, 1984, pp. 733-790.
(3) J.~. ~oyer, in "~eterocyclic Compounts", R.C. Elderfield, ed., Vol. 7, John Wiley Sons, New Yor~, 1961, pp. 384-461.

In general, the compounds of ~ormula I are constructed in such a way that Nl and N2 of the triazole ring are derived from hydrazine or a hydrazine derivative, while N4 of the triazole and the 4-(arylmethyl) substituent are derived directly or indirectly from a ~uitably substituted benzylamine.

wo 9~ gog 2 0 7 ~ ~`3 9~ CT/US91/00963 Although the reaction scheme6 described below are reasonably general, it will be understood by those 6killed in the art of organic synthesis that one or more functional groups pre6ent in a given compound of Formula I may render the molecule incompatible with a particular synthetic sequerlce.
In 6uch a case an alternative route, an altered order of 6teps, or a strategy of protection and deprotection may be employed. In all cases the particular reaction conditions, including reagents, solvent, temperature, and time, should be chosen so that they are con6istent with the nature of the functionality present in the molecule.
The Reaction Schemes below have been lS generalized for 6implicity. It is to be understood that the "ArC~2" 6ubstituent present at N4 of the triazole derivatives or in their precursors is any substituted arylmethyl moiety consistent with the definition of the N4 substituent in Formula I or which may be transformed to such a grouping either before or after the as6embly of the triazole ring system. Such transformations may involve protection and/or deprotection as shown in Formula I, or other modifications. It i8 also to be understood that in most of the Reaction Scheme6, the "ArCE2 " (Ar ~
aryl) 6ubstituent i6 con6istent with the definition of Formula I.

wo sl/119n9 2 n ~ n v ~ ~ U ~ ~ PCT~US9l/00963 ~, Abbreviations used in the scheme~ and examples below are listed in Table 1.

~.`
- Re~ents NBS N-bromosuccinimide AIBN Azobis(isobutyronitrile) DDQ Dichlorodicyanoquinone 10 Ac2o acetic anhydride TEA triethylamine DMAP 4-dimethylaminopyridine PPh3 triphenylphosphine TFA trifluoroacetic acid 15 TMS-Cl trimethylsilyl chloride Im imidazole AcSK potassium thioacetate p-TsO~ p-toluenesulfonic acid ~olvents:
DMF dimethylformamide ~OAc (AcOB') acetic acid EtOAc (EtAc) ethyl acetate 25 ~ex hexane ~F tetrahytrofuran DMSO timethylsulfoxide MeO~ methanol iPrOE i 8 opropanol .`

WO 91/1 1909 2 0 7 ~ ~`3 ~ `: Pcr/us91/00963 O~h~r~:

rt room temperature T~DMS . t-butyldimethylæilyl OTf . OSo2cF3 - Ph phenyl FAB-MS Fast atom bombardment mass ~pectroscopy NOE Nuclear Overhauser Effect 10 SiO2 silica gel trityl triphenylmethyl The compounds of the present invention may be resolved using the techniques ~nown in the art.
The diastereomeric ~alts and esters of the enantiomers are separated and the desired compound is the more active stereoisomer. The invention is intended to include individual stereoisomer6 a~ well as racemic mixture~. The compounds of thi~
invention, their pharmaceutically acceptable salts and their prodrug forms are included within the scope of this invention.
It is further to be understood that in the generalized scheme8 below, unless specified more narrowly in the text, the groups Rl and R16 represent functionalized or unfunctionalized al~yl, aryl, heteroaryl, aralkyl, and the like. The moiety R16Q
represent~ an al~ylating agent in which R16 is typically a functionalized or unfunctionalized alkyl or aralkyl group, while Q is a leaving group ~uch as chloro, bromo, iodo, methanesulfonate, or p-toluenesulfonate.

wo 9", Igog 2 0 7 5 ~ ~ 9 PCI/l)S91/00963 ~

~;~ I-l -s 1 )CS~- Et~N, ~rCH~N}~ ~CH~?~NJiNH, /~5 J
R~CN11NH, ll ll ArC~NC~I ArC}~NHCN~NHCi?' 2 ) Et ococl 4 5 ~H
~A~
o R~ ~0, b~

~Jl.

Scheme I-l outlines some of the most widely applicable routes to compounds of Formula I in which either the 3- or 5-substituent is substituted thio.
Thus an appropriate benzylamine 1 may be converted to dithiocarbamate ester 2 in a one-pot two-step sequence involving treatment with carbon disulfide in the presence of a base such as triethylamine followed by al~ylation with methyl iodide. Treatment of ~ with hydrazine ~preferably in excess) affords the 4-substituted thiosemicarbazide ~. This is also .

W091/l1909 2 ~ 3 ~ ` PCT~US91/00963 readily obtained upon reaction of hydrazine with the i60thiocyanate 4, which in turn i6 prepared from amine 1 [for e~ample, y~ an intermediate carbetho~y dithiocarbamate (J.E. ~odg~ins and M.G. Ettlinger, J.
Or~. Chem., ~1. 404 (1956)) or by one of the other methods ~nown in the literature]. The acylthiosemi-carbazide ~ may be prepared either by reaction of 3 with the appropriate acid chl-ride or anhydride or by addition of an acid hydrazide (readily obtained from lo the corresponding ester) to the isothiocyanate 4. As described in G.F. Duffin, J.D. Kendall, and ~.R.J.
Waddington, J. Chem. Soc., 3799 (1959), S.M.
El-Khawass and N.S. ~abib, J. ~eterocyclic Chem., 26, 177 (1989), and numerous other papers, acylthiosemi-carbazides related to 5 can by cyclized in thepresence of hydroxide or al~oxide to the mercapto-triazoles (best represented as triazolinethiones) corresponding to 6. Compounds of type 6 can also be prepared by direct reaction of the thiosemicarbazide derivative ~ with an appropriate acid derivative.
For e~ample, reaction of ~ with a trimethyl orthoester at elevated temperature in a suitable 60lvent (such as 2-metho~yethanol st reflu~) yields ~. Similar 6yntheses of mercaptotriazoles have been reported by G.A. Reynolds and J.A. Van Allan, 1~ ~L~
Chem., 2~. 1478 (1959~. Other acid derivatives such as esters [in thé presence of al~oxite: M. Pesson, G.
Polmanss, and S. Dupin, Compt. B~n~-. 248, 1677 (1959)] and selenoesters [V.I. Cohen, J. eterocyclic Chem., 15, 237, (197B)] have al60 been reported to react with 4-substituted thiosemicarbazides to give mercaptotriazoles analogous to 6. In certain wo91/]1909 2 0 7 ~ 6 3 9: - PCT/~S91/00963 ~

instance6 the carboxylic acid~ itself may be used.
Thu6, 4-substituted thiosemicarbazides have been reacted with trifluoroacetic acid at elevated temperature to give mercaptotriazoles analogous to (R=CF3) [T. Cebalo, U.S. Patent 3,625,951 (1971) and E.I. Aoyagi, ~.S. Patent 4,477,459 (1984)~.
The S-al~ylated mercaptotriazoles of structure 7 are obtained by treatment of the triazolinethione 6 with an appropriate alkylating agent R16Q in which R16 is functionalized or unfunctionalized alkyl, aralkyl, heterocyclyl, or the like, and Q is a leaving group such as chloro, bromo, iodo, methanesulfonate, or ~-toluenesulfonate. This alkylation i6 conducted in any of a variety of solvents (including methanol, ethanol, 2-methoxy-ethanol, tetrahydrofuran, N,N-dimethylformamide, dichloromethane and water, depending on the properties of the particular substituents) in the presence of a base (such as a trialkylamine, alko~ide, or hydro~ide). Triazolinethiones (mercaptotriazole6) are ~nown to give the S-alkylated derivatives predominantly if not exclusively under basic condition6 (see, for examples, C. Temple and J.A. Montgomery, "Triazoles: 1,2,4", Wiley-Interscience, New York, 1981, pp. 251-258).The alkylation reaction is generally run at a temperature of from O-C to 125-C., depending on the reactivity of the alkylating agent.
The triazolinethiones ~ may be prepared by alternative routes. In the method of F. Malbec, R.
Milcent, and G. Barbier t~ LQcycl Ch~mL, 21.
1689 (1984)~ (Scheme I-2), the imidate hydrochloride WO 91/11909 2 0 7 ~ ~ ~ 9 PCT/US91/00963 ,~

8 is reacted with thiosemicarbazide at ambient temperature to give the ester thiosemicarbazone 9.
The conversion of 9 to the triazolinethione 6 can be effected by heating with amiIe 1 in DMF at reflux.
Similarly, an N4-substituted ester thiosemicarbazone 2~. which i8 obtained by reaction of 8 with ~, can be cyclized to 6 by heating in the presence of a base, e.g., 1,8-diazabicyclo{5.4.0}undec-7-ene (DBU), in a solvent ~uch as tetrahydrofuran.

SCHE~ I-2 NH HCl S NNHCNH~ H
R'COEt H2NHCNH2 RlCOE ArCH2NH2 ~--N
LA~

~0 3 1I N~cH2~r . R' COEt - DBU
9o THF, a _v_ For triazolinethiones of type ~ where Rl-aryl, the method of T. Radha Vakula, V. Ranga Rao, and V.R. Srinivasan ~ ia~ J. Chem~, 7, 577 (1969)](Scheme I-3) i6 applicable. Thus the thiosemicarbazide derivative ~ is condensed with an aromatic aldehyde lQ to give the thiosemicarbazone 11- Upon treatment Of 11 with bromine in acetic acid, the triazolinethione 1~ is formed.

-WO 91/11909 2 0 7 3 ~; 3 ~ PCI/lJ~i91/00963 SC~: I-3 s ArCH~ CH~ C~:N~C~
~ 10 1 R~-aryl N--N
Br7 R~
~OH

Following the method of L. Strzemecka [Polish J. Chem., 57 561 (1983)] (Scheme I-4~, reaction of an ~midrazone 1~ with the i~othiocyanate 4 in ethanol at reflux gives triazolinethione 6.

SC~EME I-4 20 R1CNH ~HCl I ArCH2NCS ~~~~~~ Rl ~ N ~ S

13 4 Ar _ 6 Certain S-sub~tituted mercaptotriazoles of formula 7 which may not be accessible by the reactions o~ Scheme I-l (e~pecially R16~ aryl) can be prepared by an alternative route (Scheme I-5) involving di~placement of a lea~ing group on the triazole by an appropriate thiol. Treatment of the triazolinethione 6 with chlorine under anhydrous conditions in a ~ w091/ll90~ 2 0 7 ~ ~ 3-9 PCT/US9l/OOg63 ~olvent such as chloroform or dichloromethane gives as 8 major product the chlorotriazole 14 tD.S.
Deshpande, T.G. Surendra Nath, and V.R. Sriniva~an, Indian J. ~hEm., 13, B52 (1975)]. In addition, the synthe~is of chlorotriazoles by POC13/PCls treatment of the corresponding triazolinone has been reported tS- Naqui and V.R. Srinivasan, J. Sci. Industr. Res., Zl~, 195 (1962)]. Reaction of 1~ with a thiophenol or other thiol in the presence of a base such as N,N~diisopropylethylamine at elevated temperature (for example, in DMF at reflux) gives 7. Similar reactions have been reported by ~. Becker and K.
Wehner, British Patent 1,157,256 (1969).
Alternatively, the methylthiotriazole 1~ may be prepared (by al~ylation of 6 with methyl iodide) and ,~,~ Cl2 . ,~, ~Cl -- Rl~ ~SR t ~j 14 7 l~tI R~N~S~ R--~ ~S~
AcOH ~ Cl b~
Al' ', ` ~ " ' '': ' . - .
' ' ' :

, wo g~ gO9 2 0 7 ~ & 3 9 PCT/US91/00963 ~

then oxidized to the methylsulfone 1~ using hydrogen peroxide. Displacement of the methanesulfonyl group Of 1~ e the chloro group Of 1~. by R16S~ in the presence of a base afford6 7, e6pecially for Rl~ =
aryl. The preparation of a methane6ulfonyltriazole analogous to 1~ and its nucleophilic tisplacement have been reported by E.B. A~erblom and D.E.S.
Campbell, J. Med. Chem.. 1~, 312 (1973).

o ~l~k N~ N o N--N o R1--~5R1 ~ R1 _(~Rl ~ t R1 ~R' 15~Ar P~202/DAC ~Ar ~Ar or 7 R' CO~H 17 18 The S-6ubstituted mercaptotriazoles 7 can be converted to the corre6ponding 6ulfosides 17 and/or 6ulfones 1~ by o~idation with various reagents 6uch as hydrogen pero~ide in acetic acid or a cuitable peracid. Reactions of this type have been described by E.B. Akerblom and D.E.S. Campbell (see reference above). Whether 11 or 1~ is tbe primary or exclusive product depends on the stoichiometry of the reagent6, reaction time, and temperature.

~WO91/11909 2 ~ 7 S;6 3 ~` PCT/US91/00963 ~Z

.5 11 ~1 O 11 IOIR~ llrC}~
R1 COEt R' ~CNHNH
- R CO~ E:tOX ~ R1--~--R1 Ar ~9 __ The method of R. ~raft, ~. Paul, and G.
~ilgetag ~Chem, ~er.. lQl. 2028 (1968)] (Scheme I-7~
is u~eful for preparing triazoles of 6tructure 2Q in which R16 i6 aryl or heterocyclic. Treatment of the imidate hydrochloride 8 with an appropriate hydrazide (typically at -10- to 5'C.) gives the adduct l9, which can be reacted with the amine 1 and cyclized to the triazole 20 upon heating in ethanol. ~y use of the adaption of M. Pescon and M. Antoine tBUll. Soc.
Chi~. Fr., 1590 (1970)~, triazoles of type 2~ in which R16 is a substituted carboxamide group are obtained by employing a substituted osamic acid hydrazide in Scheme I-7.

~SC~EME I-8 ArC*NCS NH~ ~tC*~ ArC~ S~ R' ~NICII~
bO~D
~- 22 ~" 1l ~rC*NHCNl~MCR' DMF R~--~R" ~ ( R~ Ar i~_ ~ \ R"

.

wo 9,/1,gog 2 0 7 3 ~ 3 9 ~CT/US91/00963 ~

Aminotriazoles of formula 2~, where B is a single bond, can be prepared as shown in Scheme I-8.
An analogous route ha6 been reported by E. A~erblom, Acta Chem. Scand., 19, 1135 ~1965). Reaction of the i60thiocyanate 4 with an appropriate amine gives the thiourea ~l. which i8 al~ylated with methyl iodide to give the isothiourea ~ydriodide 22. The acylaminoguanidine 2~, obtained by reaction of 2 with a hydrazide in the presence of ba6e, can be thermally cyclized to 2~, which i6 separated from the isomeric byproduct 2~. Modest yields of aminotriazoles analogous to 24 have al60 been obtained by direct thermal reaction of intermediates analo~ous to 2~ with a hydrazide ~L. Carey, B.J.
Price, J.W. Clitherow, J. Bradshaw, M. Martin-Smith, D.~. Bays, and P. Blatcher, U.S. Patent 4,481,199 (1984)].

H~OCN~CH~r CO,H ~" ( .2 2~ 27 IN,H, K~ ' ~R"
~rC~

In another route i6 shown in Scheme I-9 following a sequence reported by L. Carey, ~ a1., U.S. Patent 4,481,199 (1984), amine 1 is heated with the S-methyl thio6emicarbazide derivative 26 to give , Wo91/11909 2 0 7 ~ ~ 3 9 PCT/VS9l/00963 ., .;~
....

the aminoguanidine 21. ~eating 21 with an appropriate carboxylic acid provides the aminotriazole 2~, which i~ separated from the isomer 2~ if present. Similar chemistry has been reported by C.F. ~roger, G. Scho~necht, and ~. Beyer, Ch~m.
~L~, 97, 396 (1964), R.G.W. Spic~ett and S.H.B.
Wright, British Patent 1,070,243 (1967), and G.J.
Durant, G.M. Smith, R.G.W. Spic~ett, and S.~.B.
Wright, J. Med. Che~., 2, 22 (1966). Thi~ last paper lo also describes the 6ynthesi6 of aminoguanidines analogous to 27 by hydrazine treatment of isothioureas corresponding to ~ ee Scheme I-8).

~NN~ RI ~N C}~ N~
~Ar ~
2~ 29 30 R'C-oryl A useful route to certain N-(arylmethyl) aminotriazoles 30 is 6hown in Scheme I-10. The aminotriazole 2~ (equivalent to ~, R'.~), which can be prepared by Scheme I-B or Scheme I-9 iB condensed with an aromatic aldehyde to give the Schiff base 22. Reduction of 22 with a suitable reducing agent such as sodium borohydride gives 30. Related syntheses of benzylaminotriazoles have been reported by Reiter tJ. Reiter, T. Somorai, P. Dvortsa~, and Gy. Bujtss, 1~ e~ocycl. Cheml, 22, 385 (1985) and J. Reiter, L. Pongo, and P. Dvort~ak, J. ~eterocvcl.
C~em , 24, 127 (1987)].

WOsl/11909 2 0 7 ~ ~ 3 ~ PCT/US91/00963 ~

, .
" .

SCEE~ I-ll 5 Rl ~ ~ Rl ~ R'~ LlA~ Rl ~ ~,R' 2~ 31 32 Following the methods of R.G. ~arrison, W.B. Jamison, W.J. Ross, and J.C. Saunders, Australian Patent Specification 518,316, aminotriazoles of structure 2~ can be heated with an acid anhydride to give the acylaminotriazoles ~1- These can be reduced with lithium aluminum hydride to give the ~-substituted aminotriazoles of formula ~.

~C~E~F~1-12 R'~ ~Cl I~NII~ N 11 ~ O
Ar A~ Ar 1 4 24 S ti Aminotriazoles of structure 24 can also be obtained by heating a chlorotriazole 1~ or a methane6ulfonyltriazole 1~ with an amine. Amine tisplacement~ on chlorotsiazole6 have been reported by E.GØ Becker and Y. Eisenschmitt, Z. Ch~m_, 8, 105 ~1968) and ~. Becker and R. Wehner, Bsitish Patent 1,157,256 (1969).

.~ WO91/l1909 2 0 7 t~ ~ 3 9 ` PCT/US91/00963 SC~EME. I-13 ~ 11 ar 0~ o~
33 a-L ~
~ ~N ~N

1 0 L,~
3~ ~ 3 Aminomercaptotriazoles of 6tructure 37 can lS be prepared as outlined in Scheme I-13, which utilize6 the chemistry of L.E. Godfrey and F. Kurzer, J. Chem. ~Q~. 5137 (1961), J. Reiter, T. Somorai, P.
Dvort6ak, and Gy. Bujta6, J. ~eterocvcl. Chem., 2~.
385 (1985), and J. Reiter, L. Pongo, and P. Dvortsak, 1~ ~cterocvclic Chem., 24, 127 (1987). Reaction of the isothlocyanate g with aminoguanidine gives 33, whlch can be cyclized in the presence of base to the aminotriazolinethione 34. Al~ylation of 34 in the presence of base yields the 5-sub6tituted derivative 1~- Further tran6formations to the Schirf base 1 and then to 37 are as in Scheme I-10.

, :.: - . . ~ ':

. .

- .. . . . : :: . . .
- , .. . . ,- .- . . . - . . . - . ::
. . .. .. . . . . . . . .

wos~9o9 ~ 0 7 ~ 6 3 9 PCT/U591/00963 ~

RI ~Cl -- R~ OR~ ~ -- R~
~Ar ~Ar ~Ar 14 3~ 16 Alkoxy and arylo~ytriazoles of formula 38 can be prepared by heating a chlorotriazole l_ or a methanesulfonyl triazole 16 with the appropriate alkoxide or phenoxide anion. Such a tran~formation has been de~cribed by E.B. Akerblom and D.E.S.
Campbell, J. Med. Chem., 1~. 312 (1973).

.- ' ~ ' . , '' :
, . , .
, -wO91/11909 2 f~ r~ s3~; PCI'/US91/00963 .;~ ~' SC~ 1-15 ~ NH2 rNHCSCH3 ~ 1~ C52. Et3N

HO 39 2) CH3I 40 rNHCNHNH2 rNHCNHN= CR' ~Rl C= N~ HCl ~ DEIU

HOEt ( 42 ) HO4 3 N~N>C5 ~ > 5 >--N ~)--N
R ~Rl~r, lPr2NEt R

` 20 ~3 ~

~C2~? R y~N~N
R 46 1) OH- ~S-R
.~
~COJ 2) H~

~` . ' -: ' '~''' : . .' .
,'' : .
.. , '' ' ' ' , ' ' . ' ~. ' ' ':
':' ' ' .''' . ~ , w091/ll9o9 2 ~ 7 5 ~ 3 ~ PCT/US91/00963 ~

In Scheme 1-15, p-hydro~ybenzylamine ~ i6 treated first at room temperature with carbon disulfide in the presence of triethylamine and then at -lO to +20-C with iodomethane to give the dithiocarbamate derivative 40. Upon heating w~th e~ces~ hydrazine in ethanol, this is tran~formed to the thio~emicarbazide 41. Reaction of ~1 with an imidate ~ in N,N-dimethylformamide (DMF) at room temperature gives the 6ubstituted ester thiosemicarbazone ~, which cyclize6 to the triazolinethione 44 upon heating with a ba6e such as l,8-diazabicyclo{5.4.0}undec-7-ene (DBU) in a suitable solvent such a6 anhydrous tetrahydrofuran (T~). Next, treatment of 44 with an al~ylating lS agent (e.g., an al~yl or aralkyl bromide) in the presence of a tertiary amine base, preferably N,N-disopropylethylamine, in a solvent such as 2-methoxyethanol generally affords the S-al~ylated deri~ative 45 a~ the primary or exclu6ive product.
This reaction is typically carried out at 20-lOO-C, dcpending on the reactivity of the al~ylating a~ent.
Treatment of 45 with the appropriate ~-bromophenylacetic acid e6ter 46 in the presence of a base such a6 anhydrous sodium carbonate or Eodium hydride in DMF or dimethyl sulfoside (DMS0) give6 an 0-al~ylated product which i6 nest saponified to the acid 47. The last step i8 accomplished by treatment of the intermcdiate ester with excess sodium or potas6ium hydroxide in aqueou~ methanol followed by acidification. A similar sequence may be carried out starting with a ring-6ubstituted 4-hydro~ybenzylamine (analog of 39)-.

. ~ wog~ s~s 2 ~ 7 ~ ~ 3 9 PCT/US91/00963 i~, The triazolinethione 44 may be prepared by alternative methods (Scheme I-16). In one of these, the thiosemicarbazide 41 i6 reacted with a trimethyl orthoester, preferably in 2-metho~yethanol at reflu~. In another method, 41 i8 treated with an acid chloride or anhydride to give the acyl derivative 48. ~eating 4B with a base such as ~odium etho~ide or hydroxide in an alcoholic or aqueous solvent results in ring clo~ure to 44 (and also removes any phenolic 0-acyl group that may be present as a by-product of the synthesis of 48).
It should be noted that a compound of ~tructure 47 may also be oxidized to the corresponding sulfoxide or sulfone by treatment with hydrogen lS pero~ide in acetic acid or with a Euitable peracid as described for Scheme 1-6. The oxidation may be carried out either before or after the ester hydrolysis of Scheme I-lS.
As 6hown in Scheme I-17, the intermediate ester 4~. prepared a6 in Scheme I-15, may be converted to a primary amide by treatment with methanolic ammonia.
~ehydration of the amide with phosphorus oxychloride in the presence of triethylamine at O-C gives the cyano derivative 50. Reaction of ~Q with trimethyltin azide in toluene at reflux, followed by removal of the trimethyltin moiety by treatment with acid and/or 5ilica gel, yields the corresponding tetrazole ~1 --wos~ 9ns 207 ~39 ` ~
a PCr/US91/00963 ~
_`~

_ 42 --SC~ 16 S
~HCN~H2 R
HO~ R1 C( OCH3 ) 3 --~N~

R1 COCl or ~\
(Rlc(=0))20 \~

S O , ~HCN~HCR1 NaOH or NaOEt - _ . . . - . -- . . ~

wos~ sos 2 0 ~ 5 ~ 3 9 PCT/US9l/00963 SC~E~ I-17 N-N
--<NlS- R~ ~
~ ~R^ 1 ) N~CHIOH
~ 2~ /Et~N~0C (~

N--N
R~ ~N~S- R' 1 ) (CH~)~SnN~tolwne/~
2) H' or ~ lllc~ g~

~ -N~N~N

A~ shown in Scheme I-18, 4-(aminomethyl)-benzoic acid (~2) can be reduced with lithium aluminum hydride or diborane to the corresponding benzyl slcohol ~, which is converted to a triazole 54 by methodE previously described. When 54 is subjected to Swern osidation condition~, the aldehyde ~ results, and this can be used to reductively al~ylate phenylalanine methyl ester in the pre~cnce of sodium cyanoborohydride. The resulting product 56 may be acylated to yield 57, which is then saponified to the free acid ~. Intermediate 56 may also be saponified. sffording ~2 ~,,., . , :

,, s WO 9~/11909 PCr/US91/00963 ,~
2075~9 '~

SC~EMI; I-18 `.
¢l or ~H~ ~ by n-thod d rcr~bod CO,H 7~F H~) ~2 ~3 Ntl Cl~ (O-)C-~ ,01 Rt L~ "
~ D~O~H~C1~
5, OH O

N--N
R~ , R~ N--H
D- Or L-P~O~ ,H RCC1 Lt,N ~J~R
NtlDH,CN~Et OH (J~7CH~ O~CH~

~ ~ ~7 ¢~) 1 ) I N~ OH ~ OH
2)J~l 2)J~l R~ R~ 7 R~ ~ T) ~- R"
~,H ~ " O
~ .
~:o H ~O~H

Or L- con~lgur-~on ' WO 91 /1 ] 909 2 Q :7 3 ~- 3 9.: Pcr/usgl/oo963 s~2 ~ N
b~ ~thod~ d-~rl~d ~k'r)b- R
ln pr~ol~ ~rn~nr~ ~ nClp ~1 R' - 8~ ( T) b- Rl ~eD~ R - E~ ~( T) b- R' ~ ~"t' ~1 2 0 ~~, ~t ,N R - 8 ~ ~ HCI R - 8 ~( ~ b- R

~ R
R ~ ~ R ~~

~3 ) ~ON R l~ b-R
~) N~ l l , ~ 0 7:5 ~ 3 3~ PCrtUS91/00963~

In Scheme I-l9, 4-nitrobenzylamine (60) i~
tran6formed to the triazole ~1 by previou~ly described methods. Stannous chloride reduction of the nitro group provide~ the amine ~2. which can be al~ylated with the ~-bromophenylacetic ester 46 to give 63. Acylation of 63 to give 64 and then saponification to 65 proceed under normal conditions. Intermediate-63 may also be directly ~aponified to give 66.
~C~EME I-20 N-~N
N-,N R - E~ ( T) ~- R'~
N~ R 1 ) 1~N,tll1,, 106t~ ,N
~ ~CN HN~

o 7 Rl~ T) R~

~) NCl ~N
R~N~ R~N~ H
¢~

- - ' ' - .

, ! . WO 91/11909 2 d 7 ~ ~ 3 9 - cr/us9l/Qo963 The aldehyde ~ may also be reacted with benzylamine and trimethyl~ilyl cyanide to give the adduct 67 (Scheme I-20). Treatment of ~1 with an acid chloride in the pre~ence of triethylamine yields the acyl derivative ~. Finally, tranb~formation of the cyano group to tetrazole by heating with trimethyltin azide afford~ the target 69.
~C~EME I-21 E!r ~

N3 ~NH, o~3 O~0 N-~J
nolbod~ ~cr~o d R -~N~L(T) b- R
ln pr-vlo~ ch-~
~L~ eY,e R~(T)b-Rt ~ N

~ R~- r71~N,~( ~) b- R
~CN ~~ KI~2 ' ~

' ' Wo91/11909 2 0 ~ 5 & 3 9 PCT/US9l/00963 ~.j In Scheme I-21, 4-methylbenzophenone (70) i6 ~-brominated with N-bromosuccinimide in the presence of a radical initiator such as benzoyl pero~ide or azobis(i60butyronitrile). The resulting bromo derivative 71 is converted to the azide 72, which is then reduced with triphenylphosphine to the amine 73. By previously described method~, 73 is transformed to the triazole 74. Treatment of 74 with a trimethylsilyl cyanide-potassium cyanide mi~ture in the presence of a crown ether yields the protected cyanohydrin ~. Upon heating 75 with excess trimethyltin azide, followed by acid treatment, the ~-hydroxy tetrazole 76 is obtained.

, .. . . .

., ~ .

~", WO91/11909 207~ 3~9 PCI/U591/00963 SCIIEM~ I-22 ~CO2H (CH3)2C=C~2 ~CO2t-E~u ~3r ~ ll250~ h~r X~

lo Br [~Co2 t - Bu ~ 1) K~L 1S-cro~
~ 2) 79 ~ 2 cCl~/~

BO [~R-CH2Br O~CO2~3u- t [~ 82 `~
W091/11909 ~
2 0 ~ PCT/US91/00963 Scheme~ I-22 and I-23 illustrate a typical ~ynthe~i~ in which the 4-(a-carbo~ybenzylo~y)benzyl side chain (6ee alRo Schemes I-lS and I-16) i~ fully con~tructed before formation of the triazole ring.
Fir~t, the appropriate phenylacetic acid 77 i~
converted to it6 t-butyl ester 78 by reaction with isobutylene in the presence of concentrated sulfuric acid, in a pres6ure vessel. Reaction of 78 with bromine under controlled condition~ yielts the a-brominated product 79. p-Cre601 (80) is converted to it~ anion (for e~ample, with potassium hydride or pota66ium t-butoxide in the presence of 18-crown-6 or with anhydrous pota66ium carbonate in DME) and treated with 79 to give ~1. Bromination with N-bromo6uccinimide in the pre6ence of azobis(i60butyronitrile) (AIBN) or benzoyl pero~ide provides 82, which i~ readily converted to the azide derivative ~ (for e~ample, with lithium azide in DMS0). U~ing the methodology of 0. T6uge, S.
~snemasa, and R. Matsuda [1.~ . Chem., 49, 2688 ~1984)], the azide ~ may be converted directly to the isothiocyanate 84 by reaction with triphenylpho6phine and carbon disulfide. Reaction of 84, which may be used without purification, with hydrazine at room temperature in a 601vent such as TgF or ethanol affords the thiosemicarbAzite ~. The ring clo6ure of ~ with trimethyl orthoformate to give ~ and the subsequent al~ylation of ~ to give 87 proceed as de8cribed for Schemes I-16 and I-15, respectively. Finally, the t-butyl protecting group in 87 is removed with trifluoroacetic acid at room temperature, and the free acit ~ is thu~ obtained.

:

,. wos~ so9 2 0 7 ~ G 3 9 : PCT/US91/00963 In a variation of Scheme I-22 analogous to a sequence in Scheme I-21, intermediate ~ i8 reduced directly to a primary amine and then converted to a triazole by one of the previously described methods.

SC~EME I-23 ~N3 ~N=C=S
~ [~

82 LlN~,O~C02BU-t Ph,P~CS, O~C02BU-t H2NNI12 D~SO l l ~ R ~ R~

N_~S
~N ~ 2 ~N~
~ S ~ r, ~PrNEC2 O~CO2Bu- t OyCO2~3u- t ~ R B5 ~ R' ~ 5~ ~

O ~ O2Bu-t ~ O2H

~R~ 8 7 (~}R- 8 8 WO91/l1909 2 0 7 5 6 3 9 PCT/US91/00963 ~

Compound6 of formula I where Z i6 -CONHS02R18 may be prepared from the corresponding carbo~ylic acid derivative6 (I) as outlined in Scheme I-24. The carbo~ylic acid (I) can be converted into the corresponding acid chloride by treatment with reflu~ing thionyl chloride or preferably with oxalylchloride and a catalytic amount of dimethylformamide at low temperature tA. W.
Burgstahler, L. 0. Weigel, and C. G. Shaefer Svnthesis, 767,(1976)]. The acid chloride then can be treated with the alkali metal salt of R18S02N~2 to form the de6ired acyl6ulfonamide ~. Alternatively, these acylsulfonamides may be also prepared from the carboxylic acids using N,N-diphenylcarbamoyl anhydride intermediates tF. J. Brown et al - ~y~o~ean Patent A~Dlication. ~P 100543; ~. L. Shepard and W.
Halczenko- J. Het. Chem., 1~, 321 (1979)].
Preferably the carbo~ylic acids can be converted into acyl-imidazole intermediates, which then can be treated with an appropriate aryl or alkylsulfonamide and diazabicycloundecene (DBU) to give the de~ired acylsulfonamide ~2 [J. T. Drummond and G. Johnson -~ g-g ~ c.- 22, 1653 (1988)].

,- Wo91/11909 ` PCT/US91/00963 ; 2~75~3~

~ ~ ~b-R~ ~r~n~ ~d--ol~ ~b_R
R'- N ~) ''-o,~r4~ D~U Rl ~
C~ -rn- - ~th~d~ Cl~
R~-~ R1 o R~, Rl o X CO~ H X CO- NH- S 0, R' r Rl~ Rl~ R
~9 *Alternative Methods:
a) (i) SOC12, reflux (ii) R18S02N~-M+ (where M is Na or Li) b) (i) (COCl)2, DMF, -20-C; (ii) Rl8S02N~-M+
c) (i) N-(N,N-Diphenylcarbamoyl)pyridinium chloride, aq. NaO~; (ii) R18S02N~-M~

Intermediate ring-substituted methyl ~-bromo-phenylacetate6 46, as used in Scheme 1-15, may be prepared as ~hown in Scheme I-25. A phenylacetic acid derivative 77, bearing one or more ring sub~tituent~, may be reacted under ~ell-Volhard-Zelins~y conditions with bromine and thionyl chloride, ~ollowed by treatment with methanol to give 46. AIternatively, a substituted benzaldehyde 89 is reacted with trimethylsilyl cyanide in the presence of potassium cyanide and 18-crown-6 to give the cyanohydrin 90. Treatment of 2Q

i.. ...

WO 91/1 1909 ~ PCI`/US91/00963 with anhydrou~ ~Cl in methanol provides the a-hydroxy ester 91. Finally, reaction of 91 with carbon tetrabromide and triphenylphosphine gives the a-bromo ester 46.
g .SC~EMl; I-25 j~ H 1 )SOCI ~r ~ IC~r Ph P
R 77 2)~0H R ~6 ¦CH C1 SlCN, ItCN
1 ~ - ~ r c~ wn- O ~- g O M~ OH .

An approach to compounds of Formula I having a 3-substituent on the benzyl portion is illustrated in Scheme I-26. A 2-substituted phenol such as 2-ethylphcnol (92) can be selectively carboxylated upon heating ~t reflux with carbon tetrachloride, 50%
aqueous sodium hydro~ide, and copper powder according to EP 193,853, to give the substituted 4-hydro~y-benzoic acid 93. Esterification of the acid followed by silylation of the phenol and lithium aluminum hydride reduction of the e6ter yields the benzyl alcohol 94. Thi6 may be converted to the benzyl bromide with carbon tetrabromide and triphenylphosphine and then to the azide 95 with lithium azide in DMS0. Triphenylphosphine reductio~
of the azide and then desilylation with tetrabutyl-ammonium fluoride gives the substituted 4-hydroxy-benzylamine derivative 96, which may be converted by the methods of Scheme I-15 to a triazole of type 97.

. . . ~ .. . .. . . . . . .. . .

, ,, ~ ,; W0 91/11909 ~ 0 7 5 ~ 3 9 PC~/US91/00963 " -~
J

SCI~ 26 Ec ~ ~ Et ~ ~_,C02H l )~O~ H2SO, HO~ ~JCCl~, 50% N~OH ;~J 2)t-Elu~2SlCl, 92Cu, ~ 93 DM~P, CH,Cl2 3)LiAlH,, THF
Et ~OH 1 )CE3r~, PH3P, CH2C12 Et ~3~N3 T~D~;-O 2)LlN3, D~SO I~D~S-O

1 ) Ph3 P, THF Et 2)H2 ~ by m~thods of 3)~u~N'F- 96 9ch~ -15 N--N
R~ R
2 0 ~,~;H

Et 97 The Claisen rearrangement of allyl phenyl ethers is another useful route to intermediates for incorporation of certain alkyl or al~enyl 6ubstituents (R9 or R10) at the 3-position of the benzyl moiety in compounds of Formula I. As an example (Scheme I-27), methyl 4-hydrosybenzoate (9R) i6 alkylated under 6tandard conditions with allyl wo 91/11909 2 ~ 7 5 ~ 3 3 PCT/USgl /00963 ~

bromide. The product 29 undergoes Claisen rearrangement to lQ0 by heating at 185-C in Q-dichlorobenzene. Silylation of the phenol, followed by hydrogenation of the allyl group in the presence of a catalyst such as rhodium on carbon, gives the n-propyl deri~ative lOl. Lithium aluminum hydride reduction of the ester then affords lQ2 By the methods described for Scheme I-26, this is converted to the sub6tituted 4-hydroxybenzylamine derivative lQ~- By employing the methods of Scheme I-15, lO~
may be transformed to a triazole of structure 104.
SC~EM~ I-27 lS

BSC
9B X~Co~, ocotonc, ~ [~l ~ 1 ~f 1 )t -~7u~SlCl, ~O
HD DMi~P, CH2Cl~ J~J LlAlH~
100 2)H~, Rh~C, 101 Et OH

by rn2t hods of ~
0 Scho~ 1-2~ HD by rnt hods of ~D~; 102 Sch~rn~ I- 7 5 R~ ~~ [~R-~O23~

::
' ' ~

. W O 91/11909 PC~r/US91/00963 Succes~ive Claisen rearrangements may be used to introduce two m-al~yl or al~enyl substituents (R9 and R10) into the benzyl moiety of a compound of Formula I. Thu~, the allyl phenol 100 from Scheme I-27 is converted to an allyl ether and then ~ubjected to a second Claisen rearrangement to give the diallyl phenol lQ~ (Scheme I-28). By the methods described for earlier 6chemes, 105 may be transformed to the 4-hydro~ybenzylamine derivative 106 and then to a triazole of structure 107.

SC~EME 1-28 1 ) ~ ~r, K~co~ by nothod HD ro-tono.
100 ~Cl ~) I-27 rnd I-2 2) W~ C lO5 }D ~J by n~t hod~ oF ~ R~
~ 9c~n~ I-lS R

'` ,. ' . ~. . . ' ' -~ u ~
wogl/]lsog PCT/US91/00963 Another e~ample of incorporation of a m-alkyl substituent (R9 or R10) on the benzyl ~roup of a compound of Formula I i6 shown in Scheme I-29.
This route is useful for the preparation of triazoles wherein the group R16 is aryl or heterocyclyl and is directly attached to the triazole ring (see al60 Scheme I-7). Intermediate lQ~ (from Scheme I-27) may be desilylated with tetrabutylammonium fluoride and then alkylated with methyl a-bromophenylacetate (46) in the presence of a base such as potassium carbonate to give lQ~. Analogous to previously described schemes, the benzylic alcohol of 108 may be replaced by bromide and then azide. Triphenylphosphine reduction of the azido group affords the benzylamine derivative lQ2. Reaction of 109 with the ester acylhydrazone 12 (from Scheme I-7) in ethanol at elevated temperature give~ the triazole llQ
Finally, the methyl ester i6 saponified to yield 111.

.

, - ' ' ' - ' . ~ .
~ .- . - .:
- .
.
: . . .

~ u (~ & ~9 ~, WO 91/11909 PCl/US91/00963 ,, , ~

SCE~EME I-2 9 ~ ~OH

~D~i o~~ F~
-- 2)46, KzCO3~ 108 Acet one ~ CO2~*
1 )C~r~, Ph3P, CH2Cl2 ~NH2 o 2)LiN3, D~SO ~ NNHCRl6 3)Ph3P, IHF~ ¦~} R' COEt 4)H20 0~/~
T EtO~l 50-70C
1 og CO2~
N--N N--N
R~ N ~--R~ Rl ~ ~_ ~ C 1 )NaOH, MaOH

The synthe6i6 of compounds of Formula I
wherein X~NR (R.alkyl, alkenyl, and the like) i6 illustrated in Scheme I-30. The ~-aminobenzyl triazole ~ (from Scheme I-19) can be protected as the ~L~-buto~ycarbonyl (~oc) derivative llZ The carbamoylated N~ may be deprotonated using a 6trong base such as 60dium hydride and then alkylated with . :
. . .

.

WO 91/1 1909 2 ~ 7 ~ PCI/US91/0~963 an appropriate al~yl (or allyl, etc.) halide.
Subseguent removal of the Boc group with trifluoroacetic acid yields the monoal~ylated aniline 1~ The aniline N~ may be deprotonated again with sodium hydride and al~ylated with the a-brOmO ester 46 to give 11~ Alternatively, 114 may be prepared from the intermediate ~ (from Scheme I-19) by deprotonation with a strong base such as lithium bis(trimethylsilyl)amide followed by treatment with the al~ylating agent RBr. ~pon saponification of the methyl ester of 114, the target compound 11~ is obtained.

S~EME 1-30 N--N N--N
N (Doc)~O Et,N R El N l)NtlH DMF

[~8 CH,Cl~
~2 ~r llZ

R' -13~ b- R ~ ~ R' - E~ R' R
~ H, DMF , <13 2 5 ~I R CO~
113 R ~l4 N--~N " / ¦~ ) NI~O~_ MeOH
R'-D--~N~ )b-R 1 )L~N(9~ 2)H~.

3R ~F / R' - EI~N~ ) b- R
-- ~ CO~ 3R
115 R CO~H

-- ' , .
: ' ` , ' ' ' . :

~. W09~ 909 2 0 7 5 ~:3 9 PCT/US9]/00963 The compounds of this invention form salts with variou6 inorganic and organic acids and bases which are also within the scope of the iDvention.
Such salt6 include ammonium salts, al~ai metal salts li~e sodium and potassium salts, al~aline earth metal 6alts like the calcium and magnesium salts, salts with organic bases; e.g., dicyclohexylamine 6alts, N-methyl-D-glucamine ~alts, salt6 with amino acids like arginine, lysine, and the like. Also, salts with organic and inorganic acids may be prepared;
g - ~Cl~ ~Br~ ~2S04~ ~3P04, methanesulfonic~
toluenesulfonic, maleic, fumaric, camphorsulfonic.
The non-toxic, physiologically, acceptable salts are preferred, although other salts are also useful;
e.g., in isolating or purifying the product.
The salts can be formed by conventional means such as by reacting the free acid or free base forms of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a 601vent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchtnge resin.
Angiotensin II (AII) i8 a powerful arterial vasoconstrictor, and it e~erts its action by interacting with specific receptors present on cell membranes. The compounds de5cribed in the present invention act as competitive antagonists of AII at 3a the receptors. In order to identify AII antagonists and determine their efficacy in vitro, the following two ligand-receptor binding assays were established.

' '. ~ ~ ' .

wo9~ 9n9 2 0 7 ~ 3-9 ` PCT/US9l/009~3 ~

Receptor binding a66ay using rabbit aortae membrane pre~atlon __ _ Three frozen rabbit aortae (obtained from Pel-Freeze Biological6) were suspended in 5 mM
Tri6-0.25M Sucrose, p~ 7.4 buffer (50 mL) homogenized, and then centifuged. The mixture was filtered through a cheesecloth and the supernatant wa6 centrifuged for 30 minutes at 20,000 rpm at 4-C. The pellet thus obtained was resuspended in 30 mL of 50 mM Tri6-5 mM
MgC12 buffer containing 0.2% Bovine Serum Albumin and 0.2 mg/mL Bacitracin ana the suspension was used for 100 assay tubes. Samples tested for screening were done in duplicate. To the membrane preparation (0.25 mL) there was added 125I-SarlIle8-angiotensin II [obtained from New England Nuclear~(10 mL; 20,000 cpm) with or without the test 6ample and the mi~ture was incubated at 37C for 90 minutes. The mi~ture was then diluted with ice-cold 50 mM Tri6-0.9% NaCl, p~ 7.4 (4 mL) and filtered through a ~las6 fiber filter (GF/B Whatman 2.4~
diameter). The filter was soaked in scintillation cocktail (10 mL) and counted for radioactivity u6ing Pac~ard 2660 Tricarb liquid scintillation counter.
The inhibitory concentration (ICsO) of potential AII
antagonist which gives 50% displacement of the total specifically bound 125I-Sar1Ile8-angiotensin II was pre~ented as a measure of the efficacy of such compounds a~ AII antagonists.

, wo g~ gog 2 0 7 ~ 6 3 9 PCT/US9l/00963 ~.. ~ .; .

Receptor assay usin~ Bovine adrenal cortex ~reparation Bovine adrenal corte~ was selected as the source of AII receptor. Weighed tis~ue (0.1 g is needed for 100 assay tubes) was suspended in Tris ~Cl (50 mM), p~ 7.7 buffer and homogenized. The homogenate was centrifuged at 20,000 rpm for 15 minutes. Supernatant was discarded and pellets resuspended in buffer [Na2~P04 (10 mM)-NaCl (120 mM)-disodium EDTA (5 mM! containing phenylmethane sulfonyl fluoride (PMSE)(0.1 mM)]. (For ~creening of compounds, generally duplicates of tubes are used).
To the membrane preparation (0.5 mL) there was added 3~-angiotensin II (50 mM) (10 mL) with or without the test sample and the mixture was incubated at 37-C for 1 hour. The mi~ture was then diluted with Tris buffer (4 mL) and filtered through a glass fiber filter (GF/B Whatman 2.4~l diameter). The filter was soaked in scintillation coc~tail (10 mL) and counted for radioactivity using Pac~ard 2660 Tricarb liquid scintillation counter. The inhibitory concentration (IC50) of potential AII antagonist which gives 50%
displacement of the total specifically bound 3~-angiotensin II was presented as a measure of the efficacy of such compounds as AII antagonists.
The potential antihypertensive effects of the compount6 described in the present invention may be evaluated using the methotology described below:
Male Charles River Sprague-Dawley rats (300-375 gm) were anesthetized with methohe~ital (~revital; 50 mgl~g i.p.) and the trachea wa~ cannulated with PE

2 0 7 ~ & 3 3 PCT/US91/00963 ~

205 tubing. A ~tainless steel pithing rod (1.5 mm thick, 150 mm long) was inserted into the orbit of the right eye and down the spinal column. The rats were immediately placed on a ~arvard Rodent Ventilator (rate - 60 6trokes per minute, volume -1.1 cc per 100 grams body weight). The right carotid artery was ligated, both left and right vagal nerves were cut, and the left carotid artery was cannulated with PE 50 tubing for drug administration, and body temperature was maintained at 37-C by a thermostati-cally controlled heating pad which received ,nput from a rectal temperature probe. Atropine (1 mg/kg i.v.) was then administered, and 15 minutes later propranolol (1 mg/~g i.v.). Thirty minutes later angiotensin II or other agonists were administered intravenously at 30 minute intervals and the increase in the diastolic blood pres6ure was recorded before and after drug or vehicle administration.
Using the methodology described above, representative compounds of the invention were evaluated and found to e~hibit an activity of at least IC50 < 50 mM thereby demon6trating and confirming the utility of the compounds of the lnvention as effective AII antagonist~.
Thus, the compounds o~ the invention are u~eful in treatin~ hypertension. They are also of value in the management of acute and chronic congestive heart failure, in the treatment of secondary hyperaldosteronism, primary and ~econdary pulmonary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure and renal ~ W091/11~09 2 ~ 7 ~ ~ 3 ~ PCT/US91/00963 vascular hypertension, and in the management of vascular disorders such as migraine or Raynaud~s disease. The application of the compound~ of this invention for these and similar disorders will be apparent to those skilled in the art.
The compounds of this invention are also useful to treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such.as tablets, capsules, injectables, as well as topical ocular formulations in the form of solutions, ointments, inserts, gels and the like.
Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 15% by weight, and preferably 0.5% to 2.~% by weight of a compound of this invention.
In the management of hypertension and the clinical conditions noted above, the compounds of this invention may be utilized in compositions such as tablets, capsules or elixirs for oral administra-tion, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular admini6tration, and the li~e. The compounds o this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of di8ease, the patient's weight, special diets then being followed by a patient, concurrent medication, and other factors which thosc s~illed in 2 ~ 7 ~ 6 3 9 PCT/US9ltO0963 ~

the art will reco~nize, the dosage range will generally be about 1 to 1000 mg per patient per day which can be administered in 6ingle or multiple doses. Perferably, the dosage range will be about 2.5 to 250 mg per patient per day; more preferably about 2.5 to 75 mg per patient per day.
The compounds of this invention can also be admini~tered in combination with other antihyperten-sives and/or diuretics and/or angiotensin converting enzyme inhibitors and/or calcium channel blocker6.
For example, the compounds of this invention can be given in combination with such compounds as amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidine sulfate, hydralazine hydrochloride, hydrochlorothiazide, metolazone, metoprolol tartate, methyclothiazide, methyldopa, methyltopate hydro-chloride, mino~idil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethlazide, trimethophan camsylate, benzthlazlde, quinethazone, tlcryna~an, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, meretho~ylline p~ocaine, sotium ethacrynate, captopril, telapril hytrochloride, enalapril, enalaprilat, fosinopril sotium, lisinopril, pentopril, quinaprll hydrochloride, ramapril, teprotide, zofenoprll calcium, diflusinal, diltiazem, felodipine, nicardipine, nifedipine, nilutipine, nimodipine, nisoldipine, nitrendipine, and the like, as well as admistures and combinations thereof.

~ WO 91/1 1909 2 0 7 ~) 6 3 9 Pcr/US9l/00963 -67~

Typically, the individual daily dosages for these combinations can range from about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given ~ingly.
To illustrate these combination~, one of the angiotensin II antagonists of this invention effective clinically in the 2.5-250 milligrams per . day range can be effectively combined at levels at - lO the 0.5-250 milligrams per day range with the following compounds at the indicated per day dose range: hydrochlorothiazide (15-200 mg), chlorothiazide (125-2000 mg), ethacrynic acid (15-200 mg), amiloride (5-20 mg), furosemide (5-80 mg), propranolol (20-480 mg), timolol maleate ~5-60 mg), methyldopa (65-2000 mg), felodipine (5-60 mg), nifedipine (5-60 mg), and nitrendipine (5-60 mg). In addition, triple drug combinations of hydrochlorothiazide (15-200 mg) plus miloride (5-20 mg) plus angiotensin II antagonist of this invention (3-200 mg) or hydrochlorothiazide (15-200 mg) plus timolol maleate (5-60) plus an angiotensin II antagonist of this invention (0.5-250 mg) or hydrochlorothiazide (15-200 mg) and nifedipine (5-60 mg) plu8 an angioten6in II antagoni6t of this invention (0.5-250 mg) are effective combinations to control blood pressure in hypertensive patients.
Naturally, these dose ranges can be adjusted on a unit basi6 as necessary to permit divided daily dosage and, as noted above, the dose will vary depending on the nature and severity of the disease, weight of patient, special diets and other factors.

.

; WO91/11909 2 0 7 5 ~ 3 ~ PC~/US91/00963 ~

Typically, these combinations can be formulated into pharmaceutical compositions as discussed below.
About 1 to 100 mg of compound or mi~ture of compounds of Formula I or a physiologically acceptable salt is compounded with a physiologically acceptable vehicle, carrier, excipient, binder, preservative, stabilizer, flavor, etc., in a unit dosage form as called for by accepted pharmaceutical practice. The amount of active substance in these compositions or preparations is 6uch that a suitable dosage in the range indicated is obtained.
Illustrative of the adjuvants which can be incorporated in tablet6, capsules and the like are the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient such as microcrystalline cellulo6e; a disintegrating agent such as corn starch, pregelatinized starch, alginic acid and the li~e; a lubricant such as magnesium stearate; a 6weetening agent such as 6ucrose, lactose or 6accharin; a flavoring agent such as peppermint, oil of wintergreen or cherry. When the dosage unitform i6 a cap6ule, it may contain, in addition to material6 of the above type, a liquid carrier 6uch as fatty oil. Various other materials may be present as coatings or to otherwi~e modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or eli~ir may contain the active compound, sucrose as a sweetening agent, methyl and propyl parabens as preservatives, a dye and a flavoring such as cherry or orange flavor.

~; WO91/11909 ~7~-~-39 PCI/US91/00963 Sterile compositions for injection can be formulated according to conventional pharmaceutical practice by dissolving or su6pending the active substance in a vehicle such as water for injection, a naturally occurring vegetable oil like sesame oil, coconut oil, peanut oil, cottonseed oil, etc., or a synthetic fatty vehicle like ethyl oleate or the like. Buffers, preservatives, antio~idants and the like can be incorporated as required.
lo The compounds of this invention are also useful tG treat elevated intraocular pressure and can be administered to patients in need of such treatment with typical pharmaceutical formulations such as tablets, capsules, injectables, as well as topical ocular formulations in the form of solutions, ointments, inserts, gels and the like. Pharmaceutical formulations prepared to treat intraocular pressure would typically contain about 0.1% to 15% by weight, and preferably 0.5% to 2.0% by weight of a compound of this invention.
Thus, the compounds of the invention are u~eful in treating hypertension. They are also of value in the management of acute and chronic conge6tive heart failure, in the treatment of secondary hyperaldosteronism, primary and secondary pulmonary hypertension, renal failure such as diabetic nephropathy, glomerulonephritis, 6cleroderma, and the like, renal vascular hypertension, left ventricular dysfunction, diabetic retinopathy, and in the management of va6cular disorders such as migraine or Raynaud's disease. The application of the compounds of this invention for these and similar disorders will be apparent to those skilled in the art.

2 0 7 ~ 6 3 9 PCT~US91/00963 ~

The useful central nervous system (CNS) activities of the compounds of this invention are demonstrated and e~emplified by the ensuing assays.

COGNITIVE FUNCTION ASS~Y

The efficacy of these compounds to enhance cognitive function can be demonstrated in a rat passive avoidance assay in which cholinomimetics such as physostigmine and nOOtrGpiC agents are known to be active. I~ this assay, rats are trained to inhibit their natural tendency to enter dark areas. The test apparatus used consists of two chambers, one of which is brightly illuminated and the other is dark. Rats are placed in the illuminated chamber and the elapsed time it takes for them to enter the darkened chamber is recorded. On entering the dark chamber, they - receive a brief electric shoCk to the feet. The test animals are pretreated with 0.2 mg/kg of the muscarinic antagonist scopolamine which disrupts learning or are treated with scopolamine and the compound which is to be tested for possible reversal of the scopolamine effect. Twenty-four hourE later, the rats are returned to the lllumlnatet chamber.
Upon return to the illuminated chamber, normal young rats who have been subjeCted to this training and who have been treated only with control vehicle take longer to re-enter the dark chamber than test animals who have been e~poset to the apparatus but who have not received a 8hock. Rat8 treatet with scopolamine before training do not show thls hesitation when tested 24 hours later. Efficacious test compounds can overcome the disruptlve effect on learning which ,~. W091/11909 ~ ~ 7 ~ ~ 3 9 PCT/US~1/00963 scopolamine produces. Typically, compounds of this invention should be efficacious in thi~ passive avoidance as6ay in the dose range of from about O.l mg/kg to about lOO mg/kg.

ANXIOLYTIC ASSAY

The anxiolytic activity of the invention compounds can be demonstrated in a conditioned emotional response (CER) assay. Diazepam is a clinically useful anxiolytic which is active in this assay. In the CER protocol, male Spra~ue-Dawley rats (250-350 g) are trained to press a lever on a variable interval (VI) 60 second schedule for food reinforcement in a standard operant chamber over weekly (five days per week) training sessions. All animals then receive daily 20 minute conditioning sessions, each session partitioned into alternating 5 minute light (L) and 2 minute dark (D) periods in a fixed LlDlL2D2L3 sequence. During both period6 (L or D), pressing a lever delivers food pellets on a VI 60 second schedule: in the dark (D), lever pre6ses also elicit mild footshock (O.B mA, 0.5 sec) on an independent 2~ shock presentatiOn schedule of VI 20 seconds. Lever pressing is suppre6sed during the dark periods reflecting the formation of a conditioned emotional re6po~se ( OE R).
Drug testing in this paradigm is carried out under e~tinction conditions. During estinction, animals learn that responding for food in the dark is no longer puni6hed by shock. Therefore, respon6e rates gradually increase in the dark periods and ~ ~ .

.:
.

WO91/11909 2 ~ 7 5 ~ 3 ~ PCT/US91/00963 ~

animals treated with an anxiolytic drug show a more rapid increase in response rate than vehicle treated animals. Compounds of this invention should be efficacious in this test procedure in the range of from about 0.l mg/kg to about l00 mg/kg.

~E2RESSION ASSAY

The antidepressant activity of the compounds of this inv~ntion can be demonstrated in a tail suspension test using mice. A clinically useful antidepressant which serves as a positive control in this assay is desipramine. The method is based on the observations that a mouse suspended by the tail shows alternate periods of agitation and immobility and that antidepressants modify the balance between these two forms of behavior in favor of agitation.
Periods of immobility in a 5 minute test period are recorded using a keypad linked to a microcomputer which allows the experimenter to assign to each animal an identity cote and to measure latency, duration and frequency of immobile periods.
Compounds of this invention should be efficacious in this test procedure in the range of from about 0.l mg/kg to about lO0 mg/kg.
.S~IZnE3~E~I~ ASSAY

The antltopaminergic acti~ity of the compounds of this invention can be demonstrated in an apomorphine-induced stereotypy model. A clinically useful antipsychotic drug that is used as a positive ~VO 91/1 1909 2 0 7 .~ PCT/US91/00963 control in this assay is haloperidol. The a3say method is based upon the ob~ervation that 6timulation of the dopaminergic system in rats produces stereo-typed motor behavior. There i8 a strong correlation between the effectivenes~ of cla~ical neuroleptic drugs to block apomorphine-induced stereotypy and to prevent schizophrenic symptom~. Stereotyped behavior induced by apomorphine, with and without pretreatment with test compounds, is recorded using a ~eypad o linked to a microcomputer. Compounds of the inven-tion should be efficacious in this assay in the range of from about 0.1 m~/kg to about 100 mg/kg.
In the treatment of the clinical conditions noted above, the compounds of thi~ invention may be utilized in compositions such as tablets, capsules or elixirs for oral administration, ~uppositories for rectal administration, sterile solutions or ~uspen-sions for parenteral or intramuscular administration, and the like. The compounds of this invention can be administered to patients (animals and human) in need of such treatment in dosages that will provide optimal pharmaceutical efficacy. Although the dose will vary from patient to patient depending upon the nature and severity of disease, the patient'~
weight, special diets then being followed by a patient, concurrent medication, and other factors which tho~e skilled in the art will recognize, the dosage range will generally be about 5 to 6000 mg.
per patient per day which can be atministered in single or multiple doses. Preferably, the dosage range will be about 10 to 4000 mg. per patient per day; more preferably about 20 to 2000 mg. per patient per day.

wo ~", Igog 2 ~ PCT~US91/00963 ~

In order to obtain maximal enhancement of cognitive function, the compounds of thi~ invention may be combined with other cognition-enhancing agents. These include acetylcholinesterase inhibitors ~uch as heptylphy60stigmine and tetrahydroacridine (T~A; tacrine), muscarinic agonists such as oxotremorine, inhibitors of angiotensin-converting enzyme such as octylramipril, captopril, ceranapril, enalapril, lisinopril, fosinopril and zofenopril, centrally-acting calcium channel blockers such as nimodipine, and nootropic agents such as piracetam.
In order to achieve optimal anxiolytic activity, the compounds of this invention may be combined with other an~iolytic agents such as alprazolam, lorazepam, diazepam, and buspirone.
In order to achieve optimal antidepressant activity, combinations of the compounds of this invention with other antidepressants are of use.
These include tricyclic antidepressants such as nortriptyline, amitryptyline and trazodone, and monoamine o~idase inhibitors ~uch as tranylcypromine.
In order to obtain ma~imal antipsychotic activity, the compounds of this invention may be combined with other antipsychotic agents such as promethazine, fluphenazine and haloperidol.
The following e~amples illustrate the preparation of the compounds of Formula I and their incorporation into pharmaceutical compositions and as such are not to be considered as limitin~ the invention set forth in the claims appended hereto.

....

, WO91/]1909 2~7~`3-9- Pcr/uSgl/00963 EXAI~LE 1 3-Butyl-4-[t4-tl-carbo~y-1-phenylmetho~y]phenyl]-methyll-5-(4-nitrobenzvlthio)-4H-1.2.4-triazole Ste~ A: Methvl ~-~4-~vdroxvbenzyl)dithiocarbamate To a ~olution of 8.4 g (33 mmol) of 4-hydro~ybenzylamine hydriodide [M. Tiffeneau, ~
Soc. Chim. Fr., 2. 819 (1911)] and 10.1 ml (7.3 g, 73 mmol) of triethylamine in 32 ml of MeO~ stirred under 0 N2 at ambient temperature was added gradually a solution of 2.2 ml (2.8 g, 38 mmol) of carbon disulfide in 12 ml of MeO~. After 1 hour, the resulting solution was cooled to -10 C and treated gradually with a solution of 2 ml (4.7 g, 33 mmol) of iodomethane in 6 ml of MeO~. The solution wa~ then stirred at room temperature for 2 hours. Next, the solution was concentrated to small volume and partitioned between ether and 0.2 ~ ~Cl. The ethereal phase was washed further with 0.2 ~ ~Cl followed by saturated NaCl. The ether solution was dried (MgSO4), filtered, and concentrated to an oil, which gratually solidified, affording 5.98 g. (85~), mp 90-91 C; homogeneous by TLC in 2:1 hexane-EtOAc.
Mass Spectrum ~FA9): 214 (M+l).
Analvsis (CgBllNOS2) calculated: C, 50.67; ~, 5.20; N, 6.57 and found: C, 50.76; ~, 5.24; N, 6.41.
1~ NMR (CDC13, 300 M~z, ppm): ~ 2.64 (s,3~), 4.81 (d,2~), 6.80 (d,2~), 6.99 (br s, 1~), 7.20 (d, 2~).

wo 9~ gog 2 0 7 ~ ~ 3 9 ` PCT/US91/0096 ~

St~ B: 4-(4-~ydroxvbenzvl)-3-thiosemicarbazide A mixture of 5.98 g (28 mmol) of methyl N-(4-hydro~ybenzyl)dithiocarbamate (product of Example 1, Step A), 27 ml (560 mmol) of hydrazine hydrate, and 72 ml of absolute EtO~ was stirred at reflux for 1 hour. The solution was purged with N2 and then concentrated. The residual oil was treated with 100 ml of C~2C12, 100 ml of ethyl acetate, and 100 ml of H2O. The solid which separated was washed first with H2O and then with ether. This material was recrystallized twice from absolute EtO~ to ~ive 2.74 g (50~ of solid, mp 179-179.5 C; homo~eneous by TLC in 19:1 C~2C12-MeO~.
Mass Spectrum (F~8): 198 (M+l).
15AnalySiS: {Cg~llN3OS 0 1 C2~6 (EtOH)}
calculated: C, 48.78; ~, 5.79; N, 20.82 found: C, 48.73; H, 5.52; N, 20.65.
(DMSO-d6, 300 M~z, ppm): ~ 4.47 (s,2~), 4.56 (d,2H), 6.68 (d,2H), 7.13 (d,2~), 8.09 (br 20s,l~), 8.67 (s,l~), 9.25 (s,l~).

!~ WO 91/1 190~ 2 0 7 ~ G 3 ~ PCr/US91/00963 .~, "

~S~ C: Ethyl Valerate 4-(4-~ydroxybenzyl)-3-thiosemicarbazone A mixture of 2.67 g (13.6 mmol) of 4-(4-hydroxybenzyl)-3-thiosemicarbazide (Example 1, Step B), 3.2 g (19 mmol) of ethyl valerimidate hydrochloride [A.J. ~ill and I Rabinowitz, J. Am.
Chem. Soc., 48, 734 (1926)], and 30 ml of dry N,N-dimethylformamide (DMF) wa6 6tirred overni~ht at room temperature under N2. It was then concentrated to small volume (oil pump, 50 C) and partitioned between ethyl acetate and ~2 The or~anic phase was washed with ~2 followed by saturated NaCl. The organic solution was dried (MgSO4), filtered, and concentrated to give a foam, which was chromatographed on a silica gel column (initial elution with C~2C12, followed by 0.5% MeO~ in C~2C12). Evaporation of the pooled product fractions yielded 928 mg (22%) of a 6tic~y white foam;
homogeneous by TLC in 19:1 C~2C12:MeO~; NMR indicated a mi~ture of ~yn and anti isomer6.
Mass S~ectrum (FAB): 310 (M~l).
~nalvsi 6 (Cl 5~23N3O2S) calculated: C, 58.22; ~, 7.49; N, 13.58 and found: C, 58.11; ~, 7.41; N, 13.34.
1~ NMR (CDC13, 300 M~z, ppm): ~ 0.89 (q,3~), 1.2-1.4 (m,5~), 1.50 (m,2~), 2.27 (m,2~
3.94,4.07 (minor and major g, total 2 8), 4.80 (d,2~), 6.80 (d,2~), 7.22 (d,2~), 7.40 (br t,l~).
7.93, 8.91 (minor and major 6, total 1~).

.
' , ~, - , .

WO91/11909 2 0 7 a 6 3 9 PCT/~S91/0096 ~

-7~-Ste~ D: 5-Butyl-2,4-dihydro-4-(4-hydroxybenzyl)-3~-1.2.4-triazole-3-thione A solution of 788 mg (2.55 mmol) of ethyl valerate 4-(4-hydro2ybenzyl)-3-thiosemicarbazone (Step C) and 761 ~1 (775 mg, 5.10 mmol) of 1,8-diazabicyclo{5.4.0}undec-7-ene (DB~) in 8 ml of dry tetrahydrofuran (TaF) wa6 stirred at reflux under N2 for 24 hour~. During thi6 time hea~y precipitation occurred. The cooled mi2ture wa~
filtered, and the solid wa~ wa~hed with T~F followed by ether. The solid (DBU 6alt of the product) was partitioned between EtOAc and 0.2 ~ ~Cl. The EtOAc phase wa~ washed with additional 0.2 ~ ~Cl and then with saturated NaCl. The EtOAc ~olution wa~ tried over MgS04, filtered, and concentrated to give 229 mg (34%) of a white solid, mp 156-157 C; homogeneou6 by TLC in 19:1 C~2C12:MeO~.
~UL5LQs~ (FAB): 264 (K+l) Analvsis (C13~17N3OS):
calculated: C, 59.29; ~, 6.51; N, 15.96 and found: C, 59.20; ~, 6.54; N, 15.59 B (DMS0-d6, 300 M~z, ppm): ~ O.78 (t,3~), 1.23 (m,2~), 1.41 (m,2~), 2.49 (t,2~), 5.11 (s,2~, 6.72 (d,Z~), 7.12 (d,2~), 9.45 (s,lE).

Step E: 3-Butyl-4-(4-hydro2ybenzyl)-5-(4-nitro-benzylthio~-4~-1.2.4-triazole A solution of 215 mg (0.82 mmol) of 5-butyl-2,4-dihydro-4-(4-hydroxybenzyl)-3~-1,2,4-triazole-3-thione (Step D) in 3 ml of 2-metho~y-ethanol was treated with 143 ml (106 mg, 0.82 mmol) of N,N-diisopropylethylamine and then with 177 mg ~' ' . ~ .

.
, , wos~ 909 2 0 ~ 3 ~ ; PCT/US9]/00963 (0.82 mmol) of 4-nitrobenzyl bromide. The solution was stirred at room temperature in a stoppered flask. ~eavy precipitation began within 30 minutes.
After 2.5 hour6, the misture was partitioned between 100 ml of EtOAc plus 10 ml of MeO~ and 100 ml of 0.2 ~Cl. The EtOAc layer was washed further with 0.2~
~Cl and then with saturated NaCl. The organic phase was dried (MgS04), filtered, and concentrated. After drying in y~5~Q (oil pump) at 50 C., there was obtained 327 mg (100%) of a solid, mp 132-133 C;
homogeneous by TLC in 97:3 C~C13-iPrO~.
Mass Spectrum (FAB): 399 (M+l) MR (DMSO-d6, 300 M~z, ppm): ~ 0.80 (t,3~), 1.25 (m,2~) 1.48 (m,2~), 2.62 (t,2~), 4.45 (s,2~), 4.93 (s,2~), 6.67 (d,2~), 6.83 (d,2H), 7.57 (d,2~), 8.15 (d,2~), 9.53 (br s, 1 ~).

Ste~ F: 3-Butyl-4-[t4-[1-(carbomethoxy)-l-phenyl-methoxy~phenyl~methyl]-5-(4-nitrobenzylthio)-4~-1.2.4-triazole A mixture of 322 mg (0.81 mmol) of 3-butyl-4-(4-hydro~ybenzyl)-5-(4-nltrobenzylthio)-4~-1,2,4-triazole (Example 1, Step E), 278 mg (1.21 mmol) of methyl ~-bromophenylacetate, 16B mg (1.22 mmol) of anhydrous K2CO3, and 3 ml of dry DM~ was stirred under N2 at 60 C for 24 hours. The mi~ture was concentrated in ~acuo (oil pump, 50-C), and the resitue was partitioned between ~tOAc and ~2 The organic solution was dried (MgS04), filtered, and concentrated. The residual oil was chromatographed on a column of silica gel (elution with a gradient of 0.5-10% MeO~ in C~2C12). TLC (97:3 C~C13-iPrO~ and .
.
~. . . .
.
'' .: ' ' ' '~ . ' ' ~ ' W09~ 909 2 a7 3 & 39 PCT/VS91/00963 98:2 C~2Cl2-MeO~) and NMR were u6ed to identify the appropriate product fractions, which were combined and concentrated to give the product as a gum.
~ss S~ectrum (FAB): 441 (M+l).
l~ B ~CDC13, 300 M~z, ppm): ~ O.84 (t,3~), 1.31 (m,2~), 1.61 (m,2~), 2.55 (t,2~), 3.71 (8,3~), 4.40 (~,2H~ 4.80 (B,2~), 5.57 (~,lH), 6.82 (6,4~), 7.25-7.55 (m,7~), 8.10 (d,2~).

Ste~ G: 3-Butyl-4-[[4-tl-carbo~y-1-phenylmethoxy]-phenyl]methyl~-5-(4-nitrobenzylthio)-4~-1.2.4-triazole A 601ution of 16 mg (0.03 mmol) of 3-butyl-4-~[4-[1-(carbomethoxy)-1-phenylmethoxy~phenyl]-methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-triazole (Example 1, Step F) in 240 ~l of C~3O~ was treated with 120 ~l (0.3 mmol) of 2.5N NaO~. After 15 minutes of stirring at room temperature, TLC
indicated complete conversion of 6tarting material to a lower Rf product. The solution was acidified to p~
1.5 by addition of 0.2N ~Cl. The precipitated ~olid was collected on a filter, washed with ~2 then with ether, and dried in vacuo over P205 to give 9.5 mg (60%) of the product a6 a solid, mp 105-106 C
(preliminary softening); homogeneous by TLC in 90:10:1 C~2Cl2:c83o~:c~3cO2~-Mass S~ectrum (F~8): 533 (M~l).
Analvsis [C2g~2gN4OsS-0.25~2O-0.25C4~1oO (ether)]:
calculated: C, 62.68; R, 5.62; N, 10.09 and found: C, 63~05; ~, 5.23; N, 9.68.

:

,-. W091/l19~9 2 ~ 7 ~ ~ 3 ~ PCT/US9l/00963 1~ NMR (CDC13, 300 M~z, ppm): ~ O~75 (t,3~), 1.20 (m,2H), 1,49 (m,2~), 2,57 (t,2H), 4.37 (8, 2H), 4.81 (ABq,2~), 5.61 (6,1~), 6.86 (ABq,4~), 7.2-7.65 (m,7~), 8.07 (d,2~.

3-Butyl-4-[[4-[1-carboxy-1-phenylmethoxy]phenyl]-methvl1-5-~4-nitrohenzylsulfinyl~-4~-1.2.4-triazole Step A: 3-Butyl-4-[[4-[1-(carbomethoxy)-1-phenyl-methoxy]phenyl]methyl]-5-(4-nitrobenzyl-sulfinvl)-4~-1.2~4-triazole A solution of 3-butyl-4-[[4-[1-(carbo-methoxy)-1-phenylmetho~y~phenyl]methyl]-5-(4-nitro-benzylthio)-4~-1,2,4-triazole (from E2ample 1, Step F) in dry CH2C12 i~ treated with m-chloroperoxy-benzoic acid (1 equivalent), and the resulting mixture is stirred at room temperature for about 30 minutes or until TLC indicates complete reaction. At this point the mi~ture i8 partitioned between ethyl acetate and saturated Na~C03 solution. The organic phase is washed repeatedly with saturated Na~C03, then dried over MgS04, filtered, and concentrated.
The residue may be purified by chromatography on silica ~el to give the title compound.

S~e~ B: 3-Butyl-4-~[4-[1-carboxy-1-phenylmethoxy]-phenyl]methyl]-5-(4-nitrobenzylsulfinyl)-4~-1.2.4-triazole By the procedure of Example 1, Step G, 3-butyl-4-~[4-[1-(carbomethoxy)-1-phenylmethoxy]-~ ' ' -wos~ gO9 2 ~ 7 ~ 6 ~ 9 PCT/US9l/00963~.i phenyl]methyl]-5-(4-nitrobenzyl6ulfinyl)-4~-1,2,4-tri-azole (from Example 2, Step A) is converted to the title compound.

E~AMPLE 3 3-Butyl-5-(4-nitrobenzylthio)-4-[[4-tl-phenyl-1-(tetrazol-5-yl)methoxy]phenyl~methyl]-4H-1,2,4-triazole Step A: 3-Butyl-4-[[4-[l-carbamoyl-1-phenylmethoxy]-phenyl]methyl~-5-~4-nitrobenzylthio)-4~-1.2.4-triazole A solution of 3-butyl-4-r[4-[l-(carbo-methoxy)-l-phenylmethoxy]phenyl]methyl]-5-(4-nitro-benzylthio)-4~-1,2,4-triazole (from Example l, Step F) in methanol is saturated with gaseous ammonia at 0- and then stirred at that temperature in a stoppered vessel for about 6 hours or until TLC
indicates complete reaction. The mi~ture is then concentrated to dryncss to yield the title compound.

.St~ 3-Butyl-4-[[4-[1-cyano-1-phenylmethoxy]-phenyl]methyl]-5-(4-nitrobenzylthio)-4~-1.2.4-triazole A 6u6pension of 3-butyl-4-[[4-[1-carbamoyl-l-phenylmethoxy]phenyl~methyl~-5-(4-nitrobenzylthio)-4~-1,2,4-triazole (from Example 3, Step A) in phosphorus oxychloride (25-30 equivalent6) i6 stirred ~o at O-C under N2 as triethylamine (2.2 eguivalents) is atded dropwise over about 1 hour. After the addition is complete, the mixture is gradually warmed to room ~ WO9l/1]909 2 0 7 ~ ~`3 9 PCT/US91/00963 temperature and then heated to reflux for about 45 minutes or until TLC indicates complete reaction.
The cooled mixture iB concentrated ~n vacuo, and the residue i~ partitioned between ice-water and an organic ~olvent, 6uch a6 ether, ethyl acetate, or toluene. The organic phase i6 washed with dilute NaO~ and then with ~2 The organic solution i~
dried over MgS04, filtered, and concentrated to give the title compound, which i6 u6ed directly or may be lo purified by chromatography on silica gel.
Step C: 3-Butyl-5-(4-nitrobenzylthio)-4-t~4~
phenyl-l-(tetrazol-5-yl)methoxy]phenyl~-methyll-4~-1.2.4-triazole A mixture of 3-butyl-4-tt4-tl-cyano-1-phenyl-methoxy]phenyl]methyl]-5-(4-nitrobenzylthio)-4~-1,2,4-triazole (from Example 3, Step B), trimethyltin azide (3.5 equivalent6), and toluene is stirred at reflux for about 2 days. The mixture is then cooled and concentrated ~n vacuo. The residue is partitioned between 0.5 ~ ~Cl and ethyl acetate.
The ethyl acetate pha~e i6 dried (MgS04), filtered, and concentrated. The residue is taken up in methanol and ~tirred with 6ilica gel (4-5 g per mmol or cyano starting material) for about 1 hour. The mixture is then evaporated Ln vacuo to give a dry powder, which i~ layered on top of a column of 6ilica gel packed in C82C12. Elution of the column with a gradient of methanol in C82C12 affords the title compound.

wos~ gog ~ ~ J ~ ~ ~ PCT/US91/0096 EXAMPL~ 4 3-Butyl-5-(4-nitrobenzyl~ulfinyl~-4-t~4-tl-phenyl-1-(tetrazol-5-yl)methoxy]phenyl]methyl]-4~-1,2,4-triazole To a stirred solution of 3-Butyl-4-tt4~
phenyl-l-(tetrazol-5-yl,methoxy]phenyl~methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole (from Example 3, Step C) in glacial acetic acid is added gradually an equal volume of 30% hydrogen peroxide (aqueous). The resulting solution is stirred at room temperature in a stoppered flask for about 15-20 hours, until TLC
and/or NMR (from wor~-up of an aliquot) indicates complete reaction. The reaction mi~ture i6 then lS partitioned between ethyl acetate and dilute ~Cl.
The ethyl acetate phase is dried (MgS04), filtered, and concentrated Ln Y~S~Q- The resitue is triturated with ether to give the title compound as a ~olid, which i~ collected on a filter and washed further with ether.

~L~

3-Butyl-4-tt4-(l-carboxy-l-phenylmethoxy)phenyl]
m~h~ll-5-~4-chlorobenzylthio~-4~-1.2.4-triazQle Step A: 3-Butyl-5-(4-chlorobenzylthio)-4-(4-hydroxy-A solution of 500 mg (1.9 mmol) of 5-butyl-2,4-dihydro-4-(4-hydroxybenzyl)-3~-1,2,4-triazole-3-thione (from Example 1, Step D) in 4 ml of 2-methoxy-ethanol was treated with 330 ~1 (245 mg; 1.9 mmol) of :` .: : ^; !`" '`
. wo 9l/l lgog 2 ~ 7 ~ ~ 3 ~ PCT/US91/00963 N~N-diisopropylethylamine and 306 mg (1.9 mmol) of 4-chlorobenzyl chloride. The misture was stirred at room temperature in a stoppered flas~ for 5 hour~ and then concentrated ~n vacuo to small ~olume. The residue was partitioned between 50 ml of EtOAc and 50 ml of 0.2 _ HC1. The organic layer was washed with an additional 50 ml of 0.2 ~ FCl followed by 50 ml of saturated NaCl. The EtOAc solution was dried over MgS04, filtered, and concentrated. The residue was chromatographed on a column of silica gel (elution with a gradient of 1 to 3% isopropanol in C~2C12) to give 411 mg (56%) of the product as a white solid, mp 149-lSO-C; homogeneous by TLC in 97:3 C~2C12-iPrO~.
Mass S~ectrum (FAB): 388 (M~l).
Analysis (C20~22ClN30S):
calculated: C, 61.92; ~, 5.72; N, 10.83 and found: C, 62.21; F, 5.79; N, 10.96 1~ NMR (DMSO-d6, 300 M~z, ppm) ~ O.81 (t, 3F), 1.26 (m, 2H), 1.48 (m, 2~), 2.57 (t, 2~), 4.30 (s, 2~), 4.B9 (s, 2~), 6.68 (d, 2~), 6.78 (d, 2~), 7.33 (ABq, 4~), 9.50 (s, 1~).

Ste~ B: 3-Butyl-4-t[4-~1-(carbomethoxy)-1-phenyl-methoxy]phenyl]methyl]-5-(4-chlorobenzyl-thio)-4a-1.2.4-triazole A ~olution of 200 mg (0.52 mmol) of 3-butyl-5-(4-chlorobenzylthio)-4-(4-hydrosybenzyl)-4~-1,2,4-triazole (from Step A) in 2 ml of dry DMF was treate~
with 21 mg (0.52 mmol) of sodium hydride (60% in oil), and the mi~ture was stirret under N2 at room temperature for a few minutes until ~2 evolution had ceased and a clear solution had resulted. To this .

wo9~ 909 207~3~
P~T/US9~/~0963~
i -.s.;

was added 119 mg (0.52 mmol) of methyl a-bromo-phenylacetate, and stirring was continued under N2 at room temperature for 10 minutes and then at 65-C
for 6 hours. The cooled mixture was treated with 1 ml of MeO~ and then concentrated Ln vacuo. The residue was partitioned between 25 ml of EtOAc and 30 ml of H20. The EtOAc phase was washed with 2 x 25 ml f ~2 and then with 25 ml of saturated NaCl! The organic solution was dried over MgS04, filtered, and lo concentrated. Column chromatography of the residue on silica gel (gradient elution with 0.75-1.2% MeOH
in CH2C12) yielded 191 mg (69~/.) of the title compound as a glass; homogeneous by TLC in 97:3 C~2C12-MeOH.
Mass Spectrum (FAB): 535 (M+).
Analvsis (C2g~30ClN303S) calculated: C, 64.97; ~, 5.64; N, 7.84 and found: C, 64.80; ~, 5.79; N, 7.69.
(CDC13, 300 M~z, ppm) ~ O.84 (t, 3~), 1.30 (m, 2~), 1.59 (m, 2~, 2.52 (t, 2~), 3.71 (s, 3~), 4.27 (s, 2~), 4.75 (s, 2~), 5.58 (s, lB), 6.80 (ABq, 4~), 7.15-7.55 (m, 9~).

: 3-Butyl-4-~t4-(1-carbosy-1-phenylmetho~y)-phenyl~methyl]-5-(4-chlorobenzylthio)-4~-1.2.4-triazole To a solution of 165 m~ (0.31 mmol) of 3-butyl-4-[t4-tl-(carbomethoxy)-1-phenylmethosy~-phenyl]methyl~-5-(4-chlorobenzylthio~-4~-1,2,4-triazole (from Step B) in 2.5 ml of MeO~ was added 1.23 ml (3.1 mmol) of 2.5 ~ NaO~. The resulting , solution was stirred at room temperature in a stoppered flask for 1 ~our and then adjusted to p~ 2 by addition of .

~;; wo sl/llsos 2 0 7 ~ 6 ~ 9 - ` PCT/US9l/00963 dilute ~Cl. The mixture was concentrated ~n vacuo to give a white ~olid, which was washed thoroughly with dilute ~Cl (p~ 2) and then dried. After further washing with Et20 and vacuum-drying over P205, 133 mg (79Z~ of the title compound was obtained as a white solid, mp 66-67-C; homogeneous by TLC in 90:10:1 C~2C12-MeOH-AcOH.
Mass S~ectrum (FAB): 522 (M+l).
Analysis (C2g~2gclN303s-o 2 ~2 0-25 C4~10 (Et20)):
calculated: C, 64.00; ~, 5.72; N, 7.72 and found: C, 63.69; ~, 5.67; N, 7.77 ~ (DMSO-d6, 300 M~z, ppm): ~ 0.80 (t, 3~), 1.24 (m, 2~), 1.48 (m, 2~), 2.59 (t, 2H), 4.30 (s, 2~), 4.96 (s, 2~), 5.81 (s, 1~), 6.90 (apparent s, 4~), 7.25-7.55 (m, 9~).

E~AMPLE 6 3-Butyl-4-t[4-(1-carbo~y-1-phenylmethoxy)phenyl]-methyll-5-(4-chlorobenzylsulfinyl~-4a-1.2.4-triazole To a 6tirred solution of 60 mg (0.11 mmol) of 3-butyl-4-t[4-[1-carboxy-1-phenylmetho~y]phenyl~-methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-triazole (from Esample 5) in O.75 ml of glacial acetic acid was adted gradually 0.75 ml of 30Z hydrogen peroxide in ~2 The solution became turbid during the addition but largely clarified within a few minutes.
After adting an addltional 4 drops of acetic acid, the mi~ture was stirred at room temperature in a 6toppered flask for 16 hours. It was then diluted with 50 ml of EtOAc and shaken with 50 ml of dilute WO91/11909 2 0 7 ~ ~ 3 9 PC~/US91/00963 ~

HCl (p~ Z.5). The aqueous phase was extracted with an additional 3 portions of EtOAc. The combined EtOAc fractions were washed once with dilute ~Cl (pE
2), then dried (MgS04), filterèd, and concentrated.
Trituration of the residue with Et20 gave a gum.
Upon decantation of the Et20 and drying ~n vac~Q, 31 mg (51%) of the title compound was obtained as a stiff foam, mp 76-78-C dec.
Mass Spec~rum (~AB): 538 (M+l).
l8 ~n~lY~i~ (C2g~2gClN304S-0.5 H20-0.1 C4~100 (Et20)):
calculated: C, 61.52; ~, 5.45; N, 7.58 and found: C, 61.56; ~, 5.40; N, 7.52.
~(DMSO-d6, 300 M~z, ppm): ~ O.80 (m, 3~), 15 1.24 (m, 2~), 1.47 (m, 2~), 2.62 (m, 2~), 4.72 (ABq, 2~), 5.23, (ABq, 2~), 5.81 (s, 1~), 6.90 (m, 4~), 7.25-7.55 (m, 9~).

~X~MPLE 7 3-Butyl-6-t~4-(1-carbo~y-1-phenylmethosy)phenyl]-met~yll-5-(4-methQ~ybenz~l~hiQ~-4a-1.2.4-triazole S~e~ A: 3-Butyl-4-~4-hydrosybenzyl)-5-(4-metho~y-benzvlthio~-4a-l.2~4-triaz-L~
Reaction of 5-butyl-2,4-dihydro-4-(4-hydroxy-benzyl)-3~-1,2,4-triazole-3-thione (from Esample 1, Step D) with 4-methosybenzyl chloride according to the procedure o~ E~ample 5, Step A, gave a 70% yield of the title compound as a solid, mp 130-131-C;
homogeneous by TLC in 95:5 C~2C12-MeO~.
Mass Spectrum (FAB): 384 (M+l) Analy~s~-l8 (C21~25N302S) w~ 91/1,gog 2 0 7 S ~ 9 PCT/US9l/00963 calculated: C, 65.77; ~, 6.57; N, 10.96 and found: C, 65.89; ~, 6.56; N, 10.77 ~ R (DMS0-d6, 300 M~z, ppm): ~ 0.81 (t, 3~), 1.26 (m, 2H), 1.48 (m, 2~), 2.57 (t, 2~), 3.73 (6, 3~), 4.24 (6, 2~), 4.87 (s, 2H), 6.67, 6.79, 6.85, 7.20 (d, each 2H), 9.48 (~, 1~).

S~ B: 3-Butyl-4-[t4-rl-(carbomethoxy)-1-phenyl-methoxy]phenyl]methyl]-5-(4-metho~ybenzyl-lo thio)-4~-1.2.4-triazole The product from Step A was converted to the title compound by the procedure of Example 5, Step B. The material was obtained in 67% yield as a gum;
homogeneous by TLC in 97:3 C~2C12-MeO~.
Mass S~ m (FAB): 532 (M+l) Analvsis (C30~33N3o4s):
calculated: C, 67.77; ~, 6.26; N, 7.91 and found: C, 67.68; H, 6.41; N, 7.75 ~ (CDC13, 400 M~z, ppm): ~ O.83 (t, 3~), 1.30 (m, 2~), 1.59 (m, 2~), 2.62 (t, 2~), 3.70, 3.77 (s, each 3~), 4.34 (s, 2~), 4.78 (R, 2~), 5.57 (s, 1~), 6.78 (d, 2~), 6.81 (ABg, 4~), 7.18 (d, 2~), 7.3-7.55 (m, 5~).

~ L: 3-~utyl-4-[t4-(l-carbosy-l-phenylmethosy)-phenyl~methyl]-5-(4-methosybenzylthio)-4~-1.2.4-triazole The product from Step B was converted to the tltle compound according to the procedure of ~ample 5, Step C. The material was obtainet in 8S% yield as a white solid, mp 78-79-C; homogeneous by TLC in 90:10:1 C~2C12-MeO~-AcO~.

WO 91/11909 2 0 7 5 & 3 9 PCr/US91/00963~

Ma~ ectrum (FAB): 518 (M+l) Analysis (C2gH31N304S-0.5 H20):
calculated: C, 66.13; H, 6.12; N, 7.98 and found: C, 65.96; H, 6.10; N, 7.97.
1~ (DMS0-d6, 300 M~z, ppm): ~ O.81 (t, 3H), 1.25 (m, 2H), 1.49 (m, 2H), 2.61 (t, 2~), 3.73 (s, 3H), 4.26 (s, 2H), 4.96 (s, 2H), 5.81 (s, 1~), 6.8-7.7 (m, 13~).

1o EXAMPLE 8 3-Butyl-4-t[4-(1-carboxy-1-phenylmethoxy)phenyl]-methyll-5-(4-methoxybenzylsulfinyl~-4E-1.2.4-triazQle By the procedure of Example 6, the title compound was prepared from 3-butyl-4-t[4-(1-carboxy-l-phenylmethoxy)phenyl]methyl]-5-(4-methoxybenzyl-thio)-4~-1,2,4-triazole (E~ample 7). The material was obtained in 65% yield as a stiff foam, mp 74-75C.
Mass S~ectrum (FAB): 534 (M+l) Analvsis (C2g~3lN305s-~2o 0-1 c4Hloo ( 2 calculated: C, 63.16; H, 6.13; N, 7.52 and found: C, 63.37; H. 6.05; N, 7.42.
la~ (DMS0-d6, 300 M~z, ppm): ~ O.80 (t, 3H), 1.23~(m, 2H), 1.48 (m, 2H), 2.60 (m, 2H), 3.75 (s, Z5 3~), 4.b4 (ABq, 2H), 5.1B (ABq, 2H), 5.80 (8, lH), 6.8-7.6 (m, 13~).

. .
:, ' . , ~
. ' '~ ' .

fi ~ wo 9~ gog 2 0 ~ 5 G 3 9 ` `~ PCT/US9]/009~3 . .- .

F`XAMPLF 9 3-Butyl-4-[[4-[1-carbosy-1-(2-chlorophenyl)methoxy]-phenyl]methyl]-5-~4-chlorobenzylthio)-4~-1,2,4-triazole Ste~ A: Preparation of methyl 2-bromo-2-(2-chloro-phenvl)acetate A mixture of 2-chlorophenylacetic acid (5.00 g, 29.3 mmol) and thionyl chloride (2.67 mL, 1.2$ eq) were heated at reflux while bromine (1.51 mL, 1.0 eq) was added from a dropping funnel over 15 minutes.
The reaction mixture was heated at reflux 19.5 hours, and then cooled to room temperature. Methanol (30 mL, 25 eq) was then added slowly, as an exotherm and violent bubbling resulted. The reaction mixture was then concentrated ~n yacuo. The residue was partitioned between water and ether and the aqueous phase was then extracted twice with ether. The combined ether portions were washed with 5% Na~S03, dried (MgS04), filteret, ant concentrated in vacuo.
The residue was purified on a silica gel flash chromato~raphy column (170 s 45 mm) eluted with 15%
ethyl acetate/hesane to yield 2.13 g (28%) of the t~tle compount, 1~ NMR (300 M~z, CDC13, ppm): ~ 3.8 (s, 3~), 5.95 (s, 1~), 7.25-7.45 (m, 3~), 7.7-7.8 (m, 1~).

.

wosl/llsos 2 07 a ~ ~ ~ PCT/US91/00963 ~
- ~i . -92-Ste~ B: 3-Butyl-4-[[4-[1-carbomethoxy)-1-(2-chloro-phenyl)metho~y]phenyl]methyl]-5-(4-chloro-benzylthio)-4~-1.2.4-triazole Reaction of 3-butyl-5-(4-chlorobenzylthio)-4-(4-hydroxybenzyl)-4~-1,2,4-triazole (from Example 5, Step A) with methyl 2-bromo-2-(2-chlorophenyl)acetate, from Step A, according to the procedure of Example 5, Step B, provided a 75% yield of the title compound as a 10 glass; homo~eneous by TLC in 97:3 CH2C12-MeOH.
Mass S~ectrum (FAB): 570 (M+l) Analvsis (C2g~2gC12N303S):
calculated: C, 61.05; H, 5.12; N, 7.37 and found: C, 60.87; H, 5.33; N, 7.45.
15 1~ (CDC13, 300 M~z, ppm): ~ O.84 (t, 3H), 1.29 (m, 2H), 1.58 (m, 2H), 2.51 (t, 2H), 3.74 (s, 3H), 4.27 (s, 2H), 4.75 (s, 2~), 6.09 (8, lH), 6.81 (ABq, 4~), 7.15-7.6 (m, 8H).

20 Ste~ C: 3-Butyl-4-~[4-~1-carbo~y-1-(2-chlorophenyl)-metho~y]phenyl]methyl]-5-(4-chlorobenzyl-thio)-4~-1.2.4-triazole The product from Step B was converted to the title compound according to the procedure o~ Example 5, Stcp C. The mat-rial was obtained in 85Z yield as a white 601id, mp 100-102-C, homogeneous by TLC in 90:10:1 CH2C12-MeOH-AcOH.

`:

~w~91tl1909 2 ~ 7 ~ ~ ~ 9 ~ PCT/US9l/00963 Mass Spectru~ (FAB): 556 (M+l) (high resolution FAB):
calculated: 555.1150 and found: 555.1239 1a NMR (DMS0-d6, 300 M~z, ppm): ~ 0.79 (t, 3~) 1.23 (m, 2~), 1.47 (m, 2~), 2.62 (t, 2~, 4.32 (s, 2~), 5.00 (s, 2~), 6.04 (s, 1~), 6.91 (m, 4~), 7.25-7.55 (m, ~H).

1o EXAMPLE 10 3-Butyl-4-[~4-[1-carboxy-1-(2-chlorophenyl)methoxy]-phenyl]methyl~-5-(4-chlorobenzylsulfinyl)-4~-1,2,4-triazole The title compound was prepared from 3-butyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]phenyl]-methyl]-5-(4-chlorobenzylthio)-4~-1,2,4-triazole (Example 9) according to the methot of Example 6.
The material was obtained in 71% yield as a stiff foam, mp 89-90-C dec. (preliminary softening).
Mass Spectrum (FAB): 572 (M+l) ~D~ly~ie (C28~27C12N304S-~20) calculated: C, 56.95; R, 4.95; N, 7.12 and ~ound: C, 56.71; ~, 4.91; N, 7.00 la ~ (DMSO-d6, 300 MRz, ppm): ~ 0.78 (m, 3R), 1.21 (m, 2~), 1.45 (m, 2~), 2.60 (m, 2~), 4.72 (ABq, 2~), 5.23 (ABg, 2~), 6.04 (s, 1~), 6.90 (m, 4~), 7.2-7.6 (m, 8~).

~ ,.., , :

WO91/11909 2 0 7 ~ ~ 3 ~ PCT/US9l/00963 ~

~LE 1 1 3-~utyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]-phenyl]methyl]-5-(4-methoxybenzylthio)-4~-1,2,4-triazole S~p A: 3-Butyl-4-~t4-[1-(carbomethoxy)-1-(2-chloro-phenyl)methoxy]phenyl]methyl]-5-(4-methoxy-benzvlthio~-4~-1.2.4-triazole lo Reaction of 3-butyl-4-(4-hydroxybenzyl)-5-(4-methoxybenzylthio)-4~-1,2,4-triazole (from Example 7, Step A) with methyl 2-bromo-2-(2-chlorophenyl)-acetate, as prepared in Example 9, Step A, according to the procedure of Example 5, Step B, gave a 62%
yield of the title compound as a glass; homogeneous by TLC in 97:3 C~2C12-MeO~.
Mass Sgectrum (FAB): 566 (M+l) Analysis (C30~32ClN304S~0.2 ~2):
calculated: C, 63,24; ~, 5.73; N, 7.38 found: C, 63.08; ~, 5.81; N, 7.47 ~ R (CDC13, 300 M~z, ppm): ~ O. 83 (t, 3~), 1.29 (m, 2~), 1.57 (m, 2~), 2.51 (t, 2~), 3.74, 3.77 (6, each 38), 4.25 (8, 2B), 4.72 (6, 2~), 6.08 (s, 1~), 6.77 (d, 2~), 6.81 (ABg, 4~), 7.15 (d, 2~), 2S 7.2-7.6 (m, 4~), Step B: 3-Butyl-4-~4-tl-carbo~y-l-(2-chlorophenyl) methoxy]phenyl]methyl]-5-(4-metho~ybenzyl-thio)-4~-1.2.4-triazole The product from Step A was converted to the title compound by the method of Example 5, Step C.

ri; WO 91/11909 2 0 7 ~ 3 9 ` PCT/USg1/00963 ... .

The material was obtained in 79% yield as ~ white 601id, mp 84-86-C; homogeneous by TLC in 90:10:1 C~12C12-MeO~-AcOI~ .
Mass S~ectLum (FAB): 552 (M+l) AnaLysi~ (C29H30ClN304S-0.5 ~2) calculated: C, 62.07; ~, 5.57; N, 7.49 and found: C, 62.30; ~, 5.70; N, 7.43.
~ (DMS0-d6, 300 M~z, ppm): ~ O.79 (t, 3~), 1.24 (m, 2H), 1.47 (m, 2~), 2.60 (t, 2~), 3.73 (s, lo 3~), 4.25 (s, 2~), 4.95 (s, 2H), 6.04 (s, 1~), 6.8-6.95 (m, 6H), 7.20 (d, 2~), 7.40 (m, 2~), 7.53 (m, 2~).

E~A~

3-Butyl-4-[[4-(l-carboxy-l-phenylmethoxy)-3-propyl-~he~yllmethvll-5-phenvl-4~-1.2.4-triazole Ste~ A: Preparation of methyl 4-(2-propen-1-yloxy)-benzoate A 2 L flask wa6 equipped with a mechanical ~tirrer, a reflux condenser and a stopper, then charged with 50.05 g (0.329 mol) of methyl 4-hydroxy-benzoate, 960 mL of acetone, 22.50 g (1.625 mol) of anhydrou6 potassium carbonate, 80.5 mL (112.6 g, 0.932 mol) of allyl bromide and the misture was 6tirred snd reflused for 14 hours. The mixture was cooled to room temperature, filtered and concentrated to an oil. The residual oil was purified by di6tillation (97-C @ 0.03 mm ~g) to afford 53.52 g (86Z) of the title compound.

W09l/ll90g 2~7~3~3 Pcr/ussJ/oos~3~g ~ (300 MHz, CDC13, ppm): ~ 3.84 (s, 3~), 4.56 (d, J=7 Hz, 2H), 5.28 (dd, J=3,12 Hz, lH), 5.40 (dd, J=3,19Hz, lH), 5.96-6.10 (m, lH), 6.90 (d, J=10 Hz, 2H), 7.96 (d, J=10 Hz, 2H).
F~ : m/e 193 (M+l).

Ste~ B: Preparation of methyl 4-hydroxy-3-(2-prop-en-l-vl)benzoate A solution of 15.05 g (78.3 mmol) of the product of Step A in 25 mL of 1,2-dichlorobenzene was magnetically stirred and refluxed (183-C) under an argon atmosphere for 18 hours. At this point, the reaction mixture was cooled to room temperature and applied to a 6 cm diameter by 18 cm silica gel flash chromatography column and eluted with 25% ethyl acetate-hexane to ~eparate the 1,2-dichlorobenzene, then with 40% ethyl acetate-hexane to elute the product. The product fractions were concentrated ~n vacuo and the residual oil was crystallized from hexane to afford 13.70 g (9lZ) of the title compound.
~ B (300 M~z, CDC13, ppm): ~ 3.42 (d, J.8 ~z, 2H), 3.8~ (s, 3H), 5.14-5.20 (m, 2H), 5.48 (s, lH), 5.94-6.06 (m, lH), 6.82 (d, J~12 Hz, lH), 7.80-7.85 (m, 2H).
F~B-MS: m/e 193 (M+l).
Step C: Preparation of methyl 4-(tert-butyldimethyl-8ilvlo~cv)-3-(2-grogen-l-vl~benzoate -To a solution of 5.168 g (26.9 mmol) of the product of Step B in 50 mL of dichloromethane was atded 4.40 mL (2.95 mmol) of triethylamine, 4.46 g - : . : .
'-, ~

. - . - . - .

,- WO 91/11909 2 ~ 7 ~ ~ 3 9 PCI/~S91/00963 . .

(2.95 mmol) of tert-butyldimethylchlorosilane,0.100 g of 4-dimethylaminopyridine, and the reaction mixture was stirred at room temperature for 2 hours. The mi~ture was then diluted with S0 mL dichloromethane, washed with 100 mL 1 N hydrochloric acid, dried (MgS04), filtered and evaporated. The re~idual oil (7.993 g, 97X) was used in the next step without further purification.
1~ NMR (300 M~z, CDC13, ppm>: ~ O.24 (s, 6H), lo 1.02 (s, 9~), 3.36 (d, J=8 ~z, 2~), 3.84 (s, 3~), 4.98-5.08 (m, 2~), 5.88-6.03 (m, 1~), 6.78 (d, J=ll ~z, 1~), 7.76-8.40 (m, 2~).
FAB-MS: m/e 307 (M~l).

Step D: Preparation of 4-(tert-butyldimethyl-silvloxy)-3-(2-~ropen-1-yl)benzvl alcohol To a magnetically 6tirred solution of 8.523 g (28.0 mmol) of the product from Step C in 35 mL of anhydrous T~F was added 15.0 mL of a 1.Q M solution f lithium aluminum hydride in T~F, and the reaction mixture was 6tirred under a nitrogen atmosphere for 2 hour~. At this point, the reaction was quenched by cautious addition of 10 mL water, the re6ulting precipitate was dissolved by addition of 1.0 N
hytrochloric acid and the product was estracted into ethyl acetate. The organic layer was separated, dried (MgS04), filtered and evaporatet ~n Ya~ to affort 7.258 g (93%) of the title compound, 1~ NMR (300 M~z, CDC13, ppm): ~ O.20 (8, 6~), 1.00 (6, 9~), 3.34 (d, Jc8 ~z, 2~), 3.84 (8, 1~), 4.57 (s, 2~), 4.97-5.07 (m, 2E), 5.88-6.03 (m, 1~), 6.86 (d, J=10 Hz, 1~), 7.05-7.14 (m, 2~).
E~ m/e 279, 261 (M+l).

wo 9~ gog 2 0 7 5 ~ 3 ~ PCT/US91/00963 ~

Preparation of 4-hydro~y-3-(2-propen-1-yl)-benzvl alcohol To a ~olution of approximately 7.26 g ~2.6 mmol) of crude 4-tert-butyldlmethylsilyloxy-3-(2-propen-l-yl)benzyl alcohol, from Step D, dissolved in 50 mL of anhydrous TEF was added 26 mL (2.6 mmol) of tetra-n-butylammonium fluoride and the reaction mixture was stirred at room temperature for 16 hours.
The mixture was then evaporated in vacuo and the lo residual oil was purified on a silica gel flash chromatography column eluted with 5% methanol/chloro-form to afford 3.386 g (79%) of the title compound as a colorless oil.
la~ (300 M~z, CDC13, ppm): ~ 2.12 (br s, lH), 3.35 (d, J=8 ~z, 2~), 4.54 (s, 3~), 5.05-5.15 (m, 2~), 5.90 (br s, 1~), 5.90-6.05 (m, 1~), 6.70 td.
J-10 ~z, 1~), 7.02-7.10 (m, 2~).
FAL-~S: m/e 165 (M+l).

Ste~ F: Preparation of 4-hydroxy-3-propylbenzyl To a solution of 0.370 g (2.25 mmol) of the product o~ Step E dis~olved in 25 mL of absolute ethanol was added 53 mg oS a 5% rhodium on carbon 2S catalyst and the misture was sha~en under a 40 psig pressure of hydrogen on a Parr apparatus. After 30 minutes, the reaction mi~ture was removed, filtered ant evaporated ~n Y~Q. ~he residue was purified on a ~ilica gel flash chromatography column eluted with 35% ethyl acetate/he~ane to afford the title compound.
~ E (300 M~z, CDC13, ppm): ~ O.95 (t, J~8 ~z, 3~), 1.55-1.68 (m, 2~), 2.22 (br s, 1~), 2.57 (t, J=8 Jz, 2~), 4.56 (s, 2~), 5.93 (br 8, 1), 6.66 (d, J-10 .' .: , . . - - . .
- ~

.
, ~ Wog"llgo9 2Q7 7 ~3~ ~ :; PCT/US91/00963 _99_ ~z, 1~), 7.00 (dd, J=2, 10 Hz, 1~), 7.08 (d, J=2 ~z, 1~) FAB-MS: m/e 167 (M+l).

Ste~ G: Preparation of methyl 2-(4-hydro~ymethyl-2-~ro~vl~henoxv~-2-~henYlacetate To a solution of 0.484 g (2.91 mmol) of the product of Step F di6solved in 12 mL of acetone were added 0.667 g (2.91 mmol) of methyl 2-bromo-2-phenyl-acetate, 0.804 g (5.82 mmol) of anhydrous K2C03 and the mixture was stirred and heated at reflu~ for 5 hours. The mixture was then cooled, filtered and evaporated ~n vacuo. The residual oil wa6 purified on a silica gel flash chromatography column eluted wi~h 30% ethyl acetate/he~ane to afford 0.756 g (83%) of the title compound.
~ (300 M~z, CDC13, ppm): ~ O.95 (t, J=8 ~z, 3~), 1.58 (br s, 1~), 1.60-1.75 (m, 2~), 2.70 (t, J=8 ~z, 2~), 3.68 (s, 3~), 4.57 (m, 2~), 5.62 (s, 1~), 6.68 (d, J=10 ~z, 1~), 7.07 (dd, J=2, 10 ~z, 1~), 7.16 (d, J=2 ~z, 1~), 7.32-7.44 (m, 3~), 7.55-7.60 (m, 2~).
E~ m/e 315 (M~l).

Step ~: Methyl 2-(4-bromomethyl-2-propylpheno~y)-2-~henylacetate A solution of 402 mg (1.28 mmol) of methyl2-(4-hydro~ymethyl-2-propylphenoxy)-2-phenylacetate, from Step G, in 4 ml of C~2C12 was treated with 510 mg (1.54 mmol) of carbon tetrabromide. The solution was stirred ~igorously under N2 at room temperature as 403 mg (1.54 mmole) of triphenylphosphine was : ' ...

`

11909 2 ~7:~ 6 ~ ~ PCT/US91/00963 ~

added portionwise. The mixture was diluted with an additional 2 ml of C~2C12 and stirred at room temperature for 2 hours. Ne~t, the mixture was filtered through Celite, and the filtrate was concentrated Ln vacuo. Flash chromatography of the residue on silica gel (gradient elution with 2.5-10%
EtoAc in hexane) afforded 184 mg (38%) of the product as a gum; satisfactory purity by TLC in 98:2 C~2C12-MeO~ .
lo Mass S~ectrum (FAB): 378 (M+l) 1~ NMR (CDC13, 400 M~z, ppm): ~ O.96 (t, 3H), 1.68 (m, 2~), 2.69 (m, 2~), 3.70 (s, 3~), 4.45 (s, 2H), 5.63 (s, 1~), 6.65 (d, 1~), 7.1-7.6 (m, 7~).

~ I: Methyl 2-(4-azidomethyl-2-propylpheno~y)-2-~henvlacetate To a solution of 45 mg (0.12 mmol) of theproduct from Step ~ in 0.37 ml of dry DMSO was added 7.3 mg (0.15 mmol) of lithium azide. The solution was stirred at room temperature under N2 for 4.5 hours. After flash chromatography on silica gel (elution with 10:1 he~ane-EtOAc), 33 mg (83%) of the title compound wa~ obtained a8 a gum; satisfactory purity by TLC in 4:1 he~ane-EtOAc.
2S Ma8s Spectrum (FAB): 340 (M~l) 1~ NMR (CDC13, 400 M~z, ppm): ~ 0.96 (t, 3~), 1.68 (m, 2~), 2.71 (t, 2~), 3.70 (6, 3~), 4.22 (s, 2N), 5.64 (8, 1~), 6.70 (d, 1~), 7.03 (dd, 1~), 7.10 (fine d, 1~), 7.35-7.45 (m, 3~), 7.57 (dd, 2~).

- .

s 2 0 7 ~ ~ 3 9 - - Pcr/US91/00963 J: Methyl 2-(4-aminomethyl-2-propylphenoxy)-2-~h~nYlace~te A solution of 185 mg (0.546 mmol) of the product from step I in 1.36 ml of T~F was treated portionwi~e with 179 mg (0.682 mmol) of triphenyl-phosphine. The solution was stirred at 40-C for 2 hours. Then 19.6 ~1 of H20 was added, and the solution wa6 stirred at room temperature under N2 overnight. The solution was concentrated La vacuo, lo and the residue was re-concentrated from CH2C12.
Column chromatography on silica gel (elution with a gradient of 1.5-10% MeO~ in C~2C12 afforded 160 mg (94%) of the product as a colorless oil; satisfactory purity by TLC in 95:5 C~2C12-MeO~.
Mass S~ectrum (FAB): 314 (M+l) 1~ NMR (CDC13, 400 M~z, ppm): ~ 0.94 (t, 3~), 1.67 (m, 2~), 2.03 (br m, 2~), 2.68 (t, 2~), 3.43 (s, 2~), 3.68 (s, 3~), 5.61 (s, 1~), 6.6-7.6 (m, 8~).

St~: Ethvl valerate benzoylhyd~azone A solution of 2.2 g (15.9 mmol) of benzoic hydrazide in 50 ml of dry EtO~ was stirred under N2 at -10-C as a solution of 2.5 g (15.1 mmol) of ethyl valerimidate hydrochlorlde tpreparcd by method of 2S A.J. ~ill and I. Rabinowitz, J. Am. Chem. Soc. 48, 734 ~1926)] in 50 ml of dry EtO~ was added dropwise over about 15 minutes. Stirring was continued at -lO-C for 3 hour8, during which time a white precipitate separated. The cold misture was f iltered through Celite, and the f iltrate was co-evaporated with C~C13 at 10-C. The residue was chromatographed twice on silica gel columns (gradient elution with wog~ gOg 207;a639 PCT/US9l/00963 0.3-5% MeOH in C~2C12) to give 951 mg (25%) of the title compound as a cream-colored semi-601id, suitable for use without further purification (TLC in 97:3 C~2C12-MeO~ NMR (CDC13, 400 M~z) was comple~, suggesting that the product iB a mixture of syn- and anti-isomers.
Mass S~ectrum (FAB): 249 (Mll) Ste~ L: 3-Butyl-4-[t4-[l-(carbomethoxy)-l-phenyl-1o metho~y]-3-propylphenyl]methyl]-5-phenyl-4~-1.2.4-triazole To a solution of 43.2 mg (0.175 mmol) of ethyl valerate benzoylhydrazone (from Step K) in 0.2 ml of ethanol was added a solution of 82 mg (0.262 mmol) of methyl 2-(4-aminomethyl-2-propylphenoxy)-2-phenylacetate (from Step J) in 0.2 ml of ethanol.
The resulting solution was stirred under N2 at 50-C
for 5.5 hours. After dilution with O.4 ml of ethanol, the solution was then stirret at ~O-C under a condenser for 13 hour6. Next, the solution was co-evaporated with C~C13. The residue was chromatographed twice on silica gel columns (gradient elution, first with 0.5-3% and then with 0.3-2% MeO~
in C~C12) to give 32 mg (37Z) o~ the title compound a8 a whlte gla~s; homogeneous by TLC in 9:1 C~2C12-MeO~ .
Mas8 Spectrum (FAB): 49B (M+l) la NMR (CDC13, 400 M~z, ppm): ~ 0.86, 0.90 (t, each 3~), 1.3S, 1.60, 1.72 (m, each 2~), 2.64 (m, 4~), 3.69 (8, 3~), 5.08 (6, 2~), 5.60 (s, 1~), 6.6-7.6 (m, 13~).

.. ~ . - :

-~ wo 9l/, ]gog ~ 0 7 5;~;3 9 Pcr/US9l/00963 Ste~ M: 3-Butyl-4-[t4-(1-carboxy-1-phenylmethoxy)-3-propylphenyl]methyl]-5-phenyl-4~-1,2,4-tri-azole To a solution of 32 mg (0.064 mmol) of the 5 product from Step L in 320 ~l of TBF was added 320 ~l (0.32 mmol) of 1~ NaOH in MeOH. The solution was stirred under N2 at room temperature overnight and then concentrated. The residue was dissolved in 1 ml of MeOH and acidified to p~ l.S by addition of l~ ~Cl 10 in MeO~. This was then concentrated, and the residue was leached with CHC13. The CHC13 e~tract was dried over anhydrous Na2S04, filtered through Celite, and evaporated Ln vacuo. The residue was chromatographed on a silica gel column (gradient elution with 2-15%
15 MeOH in CH2C12) to yield 25 mg (72%) of the title compound as a white glass; satisfactory purity by TLC
in 9:1 CH2C12-MeOB.
Mass Spectrum (FAB): 484 (M+l) AnalvSiS (C30~33N303-2/3 C~2C12) calculated: C, 68.20; H, 6.50; N, 7.78 and fount: C, 68.31; B, 6.30; N, 7.93 ~ (CD30D, 400 MH2, ppm): ~ 0.8-O.9S (m, 6H), 1.62, 1.59, 1.73, 2.63, 2.97 (m, each 2~), 5.40 (s, 2B), 5.71 (~, lH), 6.8-7.7 (m, 13B).

Claims

WHAT IS CLAIMED IS:

1. A compound of Formula I wherein:

FORMULA I

or a pharmaceutically acceptable salt thereof wherein:

R1 is:
(a) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with one or more substituents selected from the group consisting of:
i) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
1) Cl, Br, I, F, 2) (C1-C4)-alkyl, 3) (C1-C4)-alkoxy, 4) NO2, 5) CF3, 6) SO2NR2aR2a, 7) (C1-C4)-alkylthio, 8) hydroxy, 9) amino, 10) (C3-C7)-cycloalkyl, 11) (C3-C10-alkenyl; and ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, or iv) COOR2, v) -CF2CF3, or vi) -CH2CF3; and (b) perfluoro-(C1-C4)-alkyl, or (c) (C3-C6)-cycloalkyl, unsubstituted or substituted with one or more substituents from the group consisting of:
(C1-C4)-alkoxy, (C1-C4)-alkyl- thio, perfluoro-(C1-C4)-alkyl, hydroxy, or halogen (F,Cl,Br,I); and B is:
(a) a single bond, (b) -S(O)n(CH2)s-, or (c) -O-;and n is 0 to 2; and s is 0 to 5; and R2 is:
(a) H, or (b) (C1-C6)-alkyl; and R2a is:
(a) R2, (b) CH2-aryl, or (c) aryl; and (d) when R2 and R2a are alkyl substituents on the same nitrogen they can be joined to form a ring; and wherein there is more than one R2a group in the definition of a structure of Formula I they may be the same or different; and R9 and R10 are independently:
(a) H, (b) (C1-C6)-alkyl, unsubstituted or substituted with (C3-C7)-cycloalkyl, (c) (C2-C6)-alkenyl, (d) (C2-C6)-alkynyl, (e) Cl, Br, F, I, (f) (C1-C6)-alkoxyl, (g) when R9 and R10 are or. adjacent carbons, they can be joined to form an phenyl ring, (h) perfluoro-(C1-C6)-alkyl, (i) (C3-C7)-cycloalkyl, unsubstituted or substituted with (C1-C6)-alkyl, (j) aryl; and X is:
(a) -O-, (b) -S(O)n-, (c) -NR13-(d) -CH2O-, (e) -CH2S(O)n-, (f) -CH2NR13-, (g) -OCH2-, (h) -NR13CH2-, (i) -S(O)nCH2-, (j) -CH2-, (k) -(CH2)2-, (1) single bond, or (m) -CH=, wherein Y and R12 are absent forming a -C=C- bridge to the carbon bearing Z and R11; and Y is:
(a) single bond, (b) -O-, (c) -S(O)n-, (d) -NR13-, or (e) -CH2-; and Except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously is bonded to two heteroatoms (O, N, S, SO, SO2).

R11 and R12 are independently:
(a) H, (b) (C1-C6)-alkyl unsubstituted or substituted with:
(i) aryl, or (ii) (C3-C7)-cycloalkyl, (c) aryl, unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
i) Cl, Br, I, F, ii) (C1-C4)-alkyl, iii) [(C1-C5)-alkenyl]CH2-, iv) [(C1-C5)-alkynyl]CH2-, v) (C1-C4)-alkoxy, or vi) (C1-C4)-alkylthio, and (d) aryl-(C1-C2)-alkyl, wherein the aryl group is unsubstituted or substituted with 1 to 5 substitutents selected from the group consisting of:
i) Cl, Br, I, F, ii) (C1-C4)-alkyl, iii) [(C1-C5)-alkenyl]CH2-, iv) [(C1-C5 )-alkynyl]CH2-, v) (C1-C4)-alkoxy, or vi) (C1-C4)-alkylthio, and (e) (C3-C7)-cycloalkyl; and R13 is:
(a) H, (b) (C1-C6)-alkyl, (c) aryl, (d) aryl-(C1-C6)-alkyl-(C=O)-, (e) (C1-C6)-alkyl-(C=O)-, (f) [(C2-C5)-alkenyl]CH2-, (g) [(C2-C5)-alkynyl]CH2-, or (h) aryl-CH2-, and Z is:
(a) -CO2H, (b) -CO2-(C1-C6)-alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl) (e) -CONH-SO2-aryl, (f) -CONH-SO2-(C1-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent chosen from the group consisting of: -OH, -SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-(C1-C4)-alkyl, -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2; and (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, or (i) -CONHSO2NR2aR2a; and (j) -SO2NHCO-aryl, (k) -SO2NHCO-(C1-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent chosen from the group consisting of: -OH, -SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3, Cl, Br, F, I, -NO2, -CO2H, -CO2-(C1-C4)-alkyl, -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2; and (l) -SO2NHCO-(C1-C4)-perfluoroalkyl, (m) -SO2NHCO-heteroaryl, or (n) -SO2NHCONR2aR2a; and T is -S(O)n-, -O-, -NHCH2-, NHC(=O)-, -C(=O)N(R20)-, or -N(R20)-; and b is 0 or 1; and R15 is (a) H, (b) (C1-C6)-alkyl, (c) phenyl, or (d) benzyl; and R16 is (a) (C1-C10)-alkyl;
(b) substituted (C1-C10)-alkyl in which one or more substituent(s) is selected from (1) I, Br, Cl, F, (2) hydroxy, (3) (C1-C10)-alkoxy, (4) (C1-C5)-alkoxycarbonyl, (5) (C1-C5)-acyloxy, (6) (C3-C8)-cycloalkyl, (7) aryl, (8) substituted aryl in which the substituents are V and W, (9) (C1-C10)-alkyl-S(O)n, (10) (C3-C8)-cycloalkyl-S(O)n, (11) phenyl-S(O)n, (12) substituted phenyl-S(O)n in which the substituents are V and W, (13) oxo, (14) carboxy, (15) NR2R2a, (16) (C1-C5)-alkylaminocarbonyl, (17) di(C1-C5)-alkylaminocarbonyl, or (18) cyano, (c) perfluoro-(C1-C4)-alkyl, (d) (C2-C10)-alkenyl, (e) (C2-C10)-alkynyl, (f) (C3-C8)-cycloalkyl, (g) substituted (C3-C8)-cycloalkyl in which the substituent is selected from:
(1) (C1-C5)-alkyl, or (2) (C1-C5)-alkoxy, (3) (C1-C5)-alkoxycarbonyl, (4) (C1-C5)-acyloxy, (5) (C1-C5)-acyl, (6) hydroxy, (7) Br, Cl, F, I, (8) (C3-C8)-cycloalkyl, (9) aryl, (10) substituted aryl in which the substituents are V and W, (11) (C1-C10)-alkyl-S(O)n, (12) (C3-C8)-cycloalkyl-S(O)n, (13) phenyl-S(O)n, (14) substituted phenyl-S(O)n in which the substituents are V and W, (15) oxo, (16) carboxy, (17) NR2R2a, (18) (C1-C5)-alkylaminocarbonyl, (19) di(C1-C5)-alkylaminocarbonyl, or (20) cyano, (h) CO2R2a, (i) aryl, (j) substituted aryl in which the substituents are V and W, (k) aryl-(CH2)r-(M1)z-(CH2)t-(l) substituted aryl-(CH2)r-(M1)z-(CH2)t- in which the aryl group is substituted with V
and W.

(m) , (n) , (o) , (p) , or (q) , and M1 is O, S, -N(R15)-, or -C(O)-; and z is 0 or 1; and r and t are 0 to 2; and V and W are each independently selected from:
(a) H, (b) (C1-C5)-alkoxy, (c) (C1-C5)-alkyl, (d) hydroxy, (e) ((C1-C5)-alkyl)S(O)n, (f) -CN, (g) -NO2, (h) -NR2R2a, (i) ((C1-C5)-alkyl)CO-NR2R2a, (j) -CO2R2a, (k) ((C1-C5)-alkyl)CO-, (l) CF3, (m) I, Br, Cl, F, (n) hydroxy-(C1-C4)-alkyl-, (o) carboxy-(C1-C4)-alkyl-, (p) -tetrazol-S-yl, (q) -NH-SO2CF3, (r) aryl, (s) -O-CONR2R2a, (t) -NR2a-CO2R2a, (u) -NR2a-CONR2aR2a, (v) -NR2a-CON(CH2CH2)2Q, (w) -OCON(CH2CH2)2Q; or (x) -CONR2R2a; and Q1 is:
O, S(O)n, or NR2a; and R18 is:
phenyl, unsubstituted or substituted with:
V and W, (C1-C4)-alkyl, or perfluoro-(C1-C4)-alkyl; and R20 is (a) H, (b) (C1-C6)-alkyl, (c) allyl, (d) (C3-C6)-cycloalkyl, (e) (C1-C4)-acyl, (f) benzyl, or (g) phenyl; and R24 groups are independently:
(a) H, (b) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl each of which is unsubstituted or substituted with a substituent selected from the group consisting of (C3-C7)-cycloalkyl, Cl, Br, I, F, -OH, -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2, -NHSO2R25, -CO2R25, (C1-C4)-alkoxyl, (C1-C4)-alklthio, (C1-C4)-acyl, or C(=O)NH2, (c) aryl, unsubstituted or substituted with V or W, (d) aryl-(C1-C4)-alkyl, unsubstituted or substituted with V or W, R25 is:
(a) H, (b) (C1-C6)-alkyl, (c) aryl, or (d) aryl-(C1-C5)-alkyl.

2. A compound which is or a pharmaceutically acceptable salt thereof wherein:
R1 is:
(a) (C1-C6)-alkyl, (C2-C6)-alkenyl or (C2-C6)-alkynyl, each of which is unsubstituted with a substituent selected from the group consisting of:
ii) (C3-C7)-cycloalkyl, iii) Cl, Br, I, F, or iv) COOR2, v) -CF2CF3, or vi) -CH2CF3; and (b) perfluoro-(C1-C4)-alkyl, or (c) (C3-C6)-cycloalkyl; and R2 is: H, or (C1-C6)-alkyl; and R2a is: R2, benzyl, or phenyl; and when R2 and R2a are alkyl substituents on the same nitrogen they can be joined to form a ring;

R9 and R10 are independently:
H, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, C1, Br, F, I, (C1-C6)-alkoxy, aryl, or R9 and R10 join to form a phenyl ring; and X and Y are:
-CH2-, -O-, -S-, -NR13-, single bond, or -CH=, which is double bonded to the carbon bearing Z and R11, except that X and Y are not defined in such a way that the carbon atom to which Z is attached also simultaneously bonded to two heteroatoms (O, N, or S(O)n); and Z is:
(a) -CO2H, (b) -CO2-(C1-C6)-alkyl, (c) -tetrazol-5-yl, (d) -CO-NH(tetrazol-5-yl) (e) -CONH-SO2-aryl, (f) -CONH-SO2-(C1-C8)-alkyl, wherein the alkyl group is unsubstituted or substituted with a substituent selected from the group consisting of: -OH. -SH, -O(C1-C4)-alkyl, -S-(C1-C4)-alkyl, -CF3, Cl, Br, F.
I, -NO2, -CO2H -CO2-(C1-C4)-alkyl, -NH2, -NH[(C1-C4)-alkyl], -N[(C1-C4)-alkyl]2; and (g) -CONH-SO2-perfluoro-(C1-C4)-alkyl, (h) -CONH-SO2-heteroaryl, or (i) -CONHSO2NR2R2a; and R11 and R12 are independently:
H, (C1-C6)-alkyl, or aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
Br, I, Cl, F, (C1-C4)-alkyl, (C2-C4)-alkenyl, (C2-C4)-alkynyl, (C1-C4)-alkoxyl, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxyl, -NR2aR2a; and R13 is:
(a) H, (b) (C1-C6)-alkyl, (c) aryl, wherein aryl is unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Br, I, Cl, F, (C1-C4)-alkyl, (C1-C4)-alkoxy, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxy, -NR2aR2a, (c) [(C2-C5)-alkenyl]CH2-, (d) [(C2-C5)-alkynyl]CH2-, (e) aryl, wherein aryl is defined as phenyl or naphthyl, unsubstituted or substituted with 1 or 2 substituents selected from the group consisting of:
Cl, Br, I, F, (C1-C4)-alkyl, (C1-C4)-alkoxyl, NO2, CF3, SO2NR2aR2a, (C1-C4)-alkylthio, hydroxy, amino, (C3-C7)-cycloalkyl, or (C3-C10)-alkenyl, (f) aryl[(C1-C6)-alkyl]CO-, or (g) [(C1-C6)-alkyl]CO-; and T is -S(O)n-, -O-, -NHCH2-, -NHC(=O)-, -C(=O)NR20, or -N(R20)-; and b is 0 or 1; and R16 is (a) (C1-C10)-alkyl in which one or more substituent(s) is selected from the group consisting of:
hydroxy, oxo, carboxy, (C1-C5)-alkoxy-carbonyl, (C3-C8)-cycloalkyl, aryl, or substituted aryl in which the substituents are V and W, and (b) aryl, unsubstituted or substituted in which the substituents are V and W;

V and W are each independently selected from:
(a) H, (b) (C1-C5)-alkoxy, (c) (C1-C5)-alkyl, (d) hydroxy, (e) ((C1-C5)-alkyl)S(O)n, (f) -CN, (g) -NO2, (h) -NR2R2a (i) [(C1-C5)-alkyl]CO-NR2R2a, (j) -CO2R2a, (k) [(C1-C5)-alkyl]CO-, (l) CF3, (m) I, Br, Cl, F, (n) hydroxy-(C1-C4)-alkyl-, (o) carboxy-(C1-C4)-alkyl-, (p) -tetrazol-5-yl, (q) -NH-SO2CF3, (r) aryl, (s) -O-CONR2R2a, (t) NR2a-CO2R2a, (u) -NR2a-CONR2aR2a, (v) -NR2a-CON(CH2CH2)2Q, (w) -OCON(CH2CH2)2Q, or (x) -CONR2R2a; and Q is: O, S(O)n, or NR2a; and R20 is: H or (C1-C6)-alkyl.

3. A compound which is or a pharmaceutically acceptable salt thereof wherein:
R1 is (C1-C6)-alkyl; and T is S, or S(=O); and R9 and R10 are: (C1-C6)-alkyl, (C1-C6)-alkenyl or (C1-C6)-alkynyl. (C1-C4)-alkoxyl, (C3-C8)-cycloalkyl, Cl, Er, I, F, or aryl;
and X is -CH2-, O or -NR13-; and R11 is phenyl, unsubstituted or substituted with 1 to 5 substituents selected from the group consisting of:
Br, Cl, F, I, (C1-C4)-alkyl, (C1-C4)-alkoxyl, CF3, NO2-(C1-C4)-alkylthio, OH or NR2aR2a;
and R13 is: H, (C1-C6)-alkyl, [(C2-C5)-alkenyl]CH2-, [(C2-C5)-alkynyl]CH2- or aryl; and Z is carboxyl, CO2-(C1-C4)-alkyl or tetrazol-5-yl; and R16 is benzyl, unsubstituted or substituted in the 2-position or in the 4-position with a substituent selected from the group consisting of: carboxyl, (C1-C4)-alkyl, Br, Cl, F, or I, methoxy or nitro.

4. A compound which is or a pharmaceutically acceptable salt thereof.
wherein:
V is:
H, 4-Cl, 4-Br, 4-I, 4-F, 4-NO2, 4-OCH3, 4-CH3, 2-CO2H; and R9 and R10 are independently:
H, Cl, Br, F, I, (C1-C6)-alkyl, (C2-C6)-alkenyl, (C2-C6)-alkynyl, (C1-C4)-alkoxyl, (C3-C7)-cycloalkyl, and R11 is: phenyl, unsubstituted or substituted with substitutents selected from the group consisting of: H, Cl, Br, F, I, CH3, or OCH3; and X is: O or -NR13-; and R13 is: H, (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl; and Z is: carboxyl, CO2-(C1-C4)-alkyl or tetrazol-5-yl; and 5. The compound of claim 1 wherein said compound or its pharmaceutically acceptable salt is selected from the group consisting of:

3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)phenyl]-methyl]-5-(4-chlorobenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-[[4-[1-carboxy-1-phenylmethoxy]phenyl]-methyl]-5-(4-methoxybenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-(1-carboxy-1-phenylmethoxy)phenyl]methyl]-5-(4-nitrobenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]-phenyl]methyl]-5-(4-methoxybenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-[[4-[1-carboxy-1-(2-chlorophenyl)methoxy]-phenyl]methyl]-5-(4-chlorobenzylthio)-4H-1,2,4-triazole;

3-Butyl-5-(2-carboxybenzylthio)-4-[[4-(1-carboxy-1-phenylmethoxy)phenyl]methyl]-4H-1,2,4-triazole;

3-Butyl-5-(4-nitrobenzylthio)-4-[[4-[1-phenyl-1-(tetrazol-5-yl)methoxy]phenyl]methyl]-4H-1,2,4-triazole;

3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)-3-propyl-phenyl]methyl-5-(4-chlorobenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)-3-propyl-phenyl]methyl-5-(4-methoxybenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)-3,5-dipropylphenyl]methyl]-5-(4-chlorobenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)-3,5-dipropylphenyl]methyl]-5-(4-methoxybenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-[[4-[1-carboxy-1-(2,5-dibromo-3,4-dimethoxy-phenyl)methoxy]phenyl]methyl]-5-(4-chlorobenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-[[4-[1-carboxy-1-(2,5-dibromo-3,4-dimethoxy-phenyl)methoxy]phenyl]methyl]-5-(4-methoxybenzylthio)-4H-1,2,4-triazole;

4-[[[N-allyl-N-[(1-carboxy-1-phenyl)methyl]amino]-phenyl]methyl]-3-butyl-5-(4-chlorobenzylthio)-4H-1,2,4-triazole;

3-Butyl-4-[[4-(1-carboxy-1-phenylmethoxy)-3-propyl-phenyl]methyl]-5-phenyl-4H-1,2,4-triazole;

4-[[[N-allyl-N-[(1-casboxy-1-phenyl)methyl]amino]-phenyl]methyl]-3-butyl-5-(4-methoxybenzylthio)-4H-1,2,4-triazole; or 3-Butyl 4-[[[N-[(1-carboxy-1-phenyl)methyl]-N-ethyl-amino]phenyl]methyl]-5-(4-chlorobenzylthio)-4H-1,2,4-triazole.

6. A pharmaceutical composition useful in the treatment of hypertension which comprises a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of Claim 1.

7. The composition of Claim 6 which includes another antihypertensive agent selected from a diuretic, an angiotensin converting enzyme inhibitor a calcium channel blocker and a .beta.-blocker which are members selected from the group consisting of:
amiloride, atenolol, bendroflumethiazide, chlorothalidone, chlorothiazide, clonidine, cryptenamine acetates and cryptenamine tannates, deserpidine, diazoxide, guanethidine sulfate, hydralazine hydrochloride, hydrochlorothiazide, methyldopa, methyldopate hydrochloride, minoxidil, pargyline hydrochloride, polythiazide, prazosin, propranolol, rauwolfia serpentina, rescinnamine, reserpine, sodium nitroprusside, spironolactone, timolol maleate, trichlormethiazide, trimethophan camsylate, benzthiazide, quinethazone, ticrynafan, triamterene, acetazolamide, aminophylline, cyclothiazide, ethacrynic acid, furosemide, merethoxylline procaine, sodium ethacrynate, captopril, delapril hydrochloride, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, quinapril hydrochloride, ramapril, teprotide, zofenopril calcium, diflunisal, diltiazem, felodipine, nicardipine, nifedipine, niludipine, nimodipine, nisoldipine, nitrendipine, as well as admixtures and combinations thereof.

8. A method of treating hypertension which comprises administering to a patient in need of such treatment a therapeutically effective amount of a compound of Claim 1.

9. An ophthalmological formulation for the treatment of ocular hypertension comprising an ophthalmologically acceptable carrier and an effective ocular antihypertensive amount of a compound of Claim 1.

10. A method of treating ocular hypertension comprising topical ocular administration to a patient in need of such treatment of an effective ocular antihypertensive amount of a compound of Claim 1.

11. A method of treating cognitive dysfunction, anxiety, or depression comprising administering to a patient in need of such treatment, a therapeutically effective amount of a compound of
Claim 1.
CA002075639A 1990-02-13 1991-02-11 Triazole angiotensin ii antagonists incorporating a substituted benzyl element Abandoned CA2075639A1 (en)

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